ll

Review
Molecular aspects of fructose
metabolism and metabolic disease
Mark A. Herman1,2,3,* and Morris J. Birnbaum4,*
1Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, NC, USA
2Duke Molecular Physiology Institute, Duke University, Durham, NC, USA
3Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA
4Internal Medicine Research Unit, Pfizer, Cambridge, MA, USA

*Correspondence: mark.herman@duke.edu (M.A.H.), morris.birnbaum@pfizer.com (M.J.B.)

https://doi.org/10.1016/j.cmet.2021.09.010

SUMMARY

Excessive sugar consumption is increasingly considered as a contributor to the emerging epidemics of

obesity and the associated cardiometabolic disease. Sugar is added to the diet in the form of sucrose or
high-fructose corn syrup, both of which comprise nearly equal amounts of glucose and fructose. The unique
aspects of fructose metabolism and properties of fructose-derived metabolites allow for fructose to serve as
a physiological signal of normal dietary sugar consumption. However, when fructose is consumed in excess,
these unique properties may contribute to the pathogenesis of cardiometabolic disease. Here, we review the
biochemistry, genetics, and physiology of fructose metabolism and consider mechanisms by which exces-
sive fructose consumption may contribute to metabolic disease. Lastly, we consider new therapeutic options
for the treatment of metabolic disease based upon this knowledge.

INTRODUCTION has correlated with an explosion in the prevalence of cardiome-

The fixation of carbon dioxide into sugars via photosynthesis
forms the basis of Earth’s food web. Heterotrophs cannot syn-
thesize their own sugars; therefore, they evolved to use plant-
derived sugars for energetic and synthetic purposes. Sucrose,
the predominant circulating sugar in plants, is composed of
equal parts of glucose and fructose. Glucose is the major circu-
lating sugar in animals, and the amount of fructose is negligible in
comparison. Glucose is a primary energetic and synthetic fuel for
most tissues and cell types in the body. In contrast, the fructose
component of the ingested sucrose is rapidly cleared by the in-
testines and liver and is catabolized for energetic purposes, con-
verted to glucose and its polymeric storage form, glycogen, or to
fatty acids and is stored as triglycerides. Despite its low levels in
the circulation, fructose serves as a signal of the ingested dietary
sugar. The differences by which glucose and fructose are sensed
and metabolized are of fundamental importance to the re-
sponses to normal physiological sugar consumption as well as
the pathophysiological consequences of excessive ingestion.
We are amid a major emergence of obesity, diabetes, and
associated cardiometabolic diseases, including non-alcoholic
fatty liver disease (NAFLD). The etiology of these epidemics is
multifactorial and depends on the interactions between genetics
and environmental factors, including diet and physical activity.
Concerns that excessive consumption of sugary foods and bev-
erages might contribute to the development of obesity and dia-
betes date back as far as the first millennium BCE and remerge
periodically throughout modern history (Emerson and Larimore,
1924; Johnson et al., 2017). In the last half century, enhanced in-
dustrial processes and corn subsidies increased the availability
of sugar, particularly in the form of sweetened beverages. This
tabolic diseases, refocusing public health attention on this issue
(Bray et al., 2004; Malik et al., 2010).
Sugar is added to beverages and food products in the form of
sucrose or the industrial product high-fructose corn syrup
(HFCS), which is manufactured by digestion of corn starch to
its glucose monosaccharides by microbial enzymes. Microbial
xylose isomerase then catalyzes the conversion of some portion
of the glucose monosaccharides to fructose. ‘‘HFCS 55,’’ the
most common formulation added to beverages, consists of
55% fructose and 45% glucose. Sucrose is ingested as a disac-
charide and requires cleavage to its monosaccharide constitu-
ents, glucose and fructose, prior to absorption. This is catalyzed
by the enzyme sucrase-isomaltase, which is localized to the in-
testinal lumen’s brush-border membrane (Hauri et al., 1979). In
contrast, the sugars in HFCS are ingested as monosaccharides
and require no further processing prior to absorption. The differ-
ences in monosaccharide versus disaccharide content of HFCS
versus sucrose could differentially affect the rate of absorption of
these sugars, which might result in distinct biological effects (Le
et al., 2012). However, compelling data that sucrose and HFCS
impart distinct metabolic effects on humans are lacking (Stan-
hope et al., 2008).
The contribution of natural dietary sugar and added sugars to
the epidemics of cardiometabolic disease remains controversial
(Khan and Sievenpiper, 2016; Stanhope, 2016; Ter Horst and
Serlie, 2017). The epidemiological correlations between different
sugar exposures and outcomes, including energy intake, weight
gain, type 2 diabetes (T2D), dyslipidemia, insulin resistance, hy-
pertension, hyperuricemia, and dental caries, tend to be less
consistent for measurements of total sugars and more consis-
tent for measurements of free and added sugars (Dhingra

Cell Metabolism 33, December 7, 2021 ª 2021 Elsevier Inc. 2329

 ll
et al., 2007; Green et al., 2014; Haslam et al., 2020; Imamura
et al., 2015; Jayalath et al., 2015; Khan and Sievenpiper, 2016;
de Koning et al., 2012; Mela and Woolner, 2018). Consumption
of fruit, the major natural source of dietary sugar, is associated
with healthy outcomes, although fruit consumption is often asso-
ciated with other healthy lifestyle choices (Khan and Sievenpiper,
2016). Sugar-sweetened beverages (SSBs) are the largest con-
tributors to added sugar and fructose intake in children and
adults (U.S. Department of Agriculture and U.S. Department of
and Health and Human Services, 2020; Virani et al. 2020), and
their consumption consistently associates with increased cardi-
ometabolic risk (Dhingra et al., 2007; Green et al., 2014; Haslam
et al., 2020; de Koning et al., 2012; Ma et al., 2015, 2016; Malik
et al., 2013; McKeown et al., 2018; Xi et al., 2015; Yoshida
et al., 2007; Zhang et al., 2020), including the excess cardiome-
tabolic deaths associated with poor diet (Coffee and Caffeine
Genetics Consortium et al., 2015).
Recommendations from public health organizations and pol-
icy makers to reduce sugar consumption have met with modest
success over the last decade. Approximately 50% of adults and
100% of youths report consuming at least one SSB per day, a
level of sugar consumption that is associated with adverse car-
diometabolic risk factors (Bailey et al., 2018; Rosinger et al.,
2017; Virani et al., 2020). Moreover, consumption of added
sugars, even at the upper limits of recent dietary recommenda-
tions, may adversely impact health (Stanhope et al., 2011). Pop-
ulations with greater food insecurity and certain ethnic or racial
subgroups report even higher intakes of SSB (Virani et al.,
2020; Zagorsky and Smith, 2020). SSB consumption has
increased during the COVID-19 pandemic (Flanagan et al.,
2021). Although public health efforts to reduce sugar consump-
tion are warranted, an improved understanding of the mecha-
nisms by which SSBs and their constituent sugars contribute
to disease is paving the way for new therapeutic strategies.
These mechanisms and strategies will be the focus of this
review.
SWEET TASTE PERCEPTION
Animals have evolved complex mechanisms to sense sugar and
motivate its consumption. Monosaccharides, including glucose
and fructose, as well as disaccharides, such as sucrose, potently
activate the G protein-coupled receptors Tas1R2 and Tas1R3,
which are located on the epithelial cells of the tongue and palate
(Nelson et al., 2001; Zhao et al., 2003). These receptors stimulate
neuronal circuitry, projecting to regions of the amygdala involved
in processing hedonic and aversive stimuli (Wang et al., 2018).
Some investigators have proposed that sugar has addictive
properties by modulating mesolimbic dopaminergic reward cir-
cuitry (Avena et al., 2008; Leigh and Morris, 2018; Lustig,
2010). Indeed, the sweetness of both caloric and noncaloric
sweeteners can induce or increase the consumption of neutral
or aversive substances, such as alcohol, in strains of mice that
otherwise avoid it (Yoneyama et al., 2008). Nevertheless,
compelling data for the ‘‘addictive’’ potential of sugar in humans
are lacking (Leigh and Morris, 2018; Markus et al., 2017).
Mechanisms in addition to sweet taste contribute to the moti-
vation for sugary food consumption. Mice with deficiency of both
Tas1R2 and Tas1R3 cannot taste sugar or other sweeteners, yet
2330 Cell Metabolism 33, December 7, 2021
Review
they learn to prefer foods that are high in glucose content, but not
fructose or other noncaloric sweeteners (de Araujo et al., 2008;
Sclafani et al., 2014). This form of sugar preference requires
the intestinal sodium-glucose cotransporter (SLC5A1, also
known as SGLT1), the principal transporter expressed by both
enterocytes and enteroendocrine cells that is responsible for
the uptake of glucose and galactose across the luminal intestinal
membrane (Dyer et al., 2005; Gorboulev et al., 2012; Tan et al.,
2020). The SGLT1-dependent effects on sugar consumption
are mediated by signals carried by the vagus nerve to activate
neurons in the caudal nucleus of the solitary tact, a region previ-
ously implicated in transducing gut sensations to the brain (Han
et al., 2018; Kaelberer et al., 2018; Tan et al., 2020). However,
recent work in an alternative ‘‘tasteless’’ genetic mouse model
missing the P2X2 and P2X3 purinergic receptors that are
required for taste cell signaling to gustatory nerves suggests
alternative forms of post-ingestive sugar sensing (Andres-Her-
nando et al., 2020a; Sclafani and Ackroff, 2021). These studies
show that fructose can enhance sugar consumption indepen-
dent of taste. The combination of sweet taste sensation and
post-ingestive sugar sensing likely interacts to robustly reinforce
preferences for sugar-rich foods.
EXCESSIVE FRUCTOSE CONSUMPTION CAN CAUSE
METABOLIC DISEASE
In the 1960s, observations that diets high in fructose can induce
hypertriglyceridemia in animals and humans in a matter of days
much more robustly than diets containing comparable amounts
of starch or glucose led to interest in fructose as a contributor to
metabolic disease (Macdonald, 1966; Nikkila € and Ojala, 1965).
Carbohydrate- and sugar-induced hypertriglyceridemia was
also strongly associated with hyperinsulinemia in humans and
in animal models of obesity and overnutrition (Eaton and Kipnis,
1969; Farquhar et al., 1966; Reaven et al., 1979; Reiser and Hall-
frisch, 1977). Subsequent studies showed that very-high-fruc-
tose diets could induce numerous dysmetabolic features,
including hypertension, that were typical of the ‘‘metabolic syn-
drome,’’ more recently known as a syndrome of cardiometabolic
disease (Hwang et al., 1987; Reaven, 1988; Sleder et al., 1980;
Tobey et al., 1981). Although these studies were instrumental
in demonstrating the potential for fructose as a cause of meta-
bolic disease, they often used fructose exposures that exceeded
50% of the total energy, far exceeding typical consumption by
humans. Fructose accounts for
9% of energy intake in the
US, and even consumers in the 95th percentile consume

15% of their energy as fructose (Marriott et al., 2009). Never-
theless, diets unphysiologically high in fructose may be useful
for identifying molecular mechanisms relevant for common
forms of diet-induced metabolic diseases.
In recent decades, interventional studies spanning weeks to
months have shown that overfeeding moderate to high doses
of sugars containing fructose can adversely impact metabolic
outcomes in humans. In the longest of such an interventional
study, Maersk and colleagues found that adding one liter of
SSB daily for 6 months increased visceral, liver, and ectopic
fat (Maersk et al., 2012). These increases were not observed in
those consuming isocaloric skim milk, noncaloric diet, soda, or
water (Maersk et al., 2012). Adding SSBs ranging from 10% to

Review
25% of energy requirements dose-dependently increased car-
diovascular risk factors, including lipids and uric acid, over a
2-week period (Stanhope et al., 2015).
With respect to potential adverse effects of fructose, Taskinen
et al. reported that a moderate increase in fructose consumption
(75 g or 300 kcal per day) in men with obesity for 12 weeks
increased body weight, liver fat, hepatic de novo lipogenesis
(DNL), and other cardiovascular risk factors (Taskinen et al.,
2017). A pivotal study by Stanhope et al. compared the effects
of adding isocaloric glucose- and fructose-sweetened bever-
ages, constituting 25% of the basal energy requirement over
10 weeks in adults who were overweight or obese (Stanhope
et al., 2009). Both interventions increased body weight to a
similar degree. However, fructose, but not glucose, increased
visceral adiposity, DNL, an atherogenic dyslipidemia, and
indices of insulin resistance (Stanhope et al., 2009). Whereas
this study provides evidence that added fructose is more delete-
rious than added glucose, a recent report from the same group
revealed that fructose and glucose in combination may be
more harmful than fructose alone (Hieronimus et al., 2020). Fruc-
tose supplementation to 25% of the energy requirement pro-
duced the strongest effect on increasing circulating triglycerides,
whereas the combination of fructose and glucose in HFCS eli-
cited a greater increase in LDL-cholesterol and circulating apoli-
poprotein B levels. This result demonstrates the potential for
complex interactions between distinct sugars. Similar interac-
tions also likely occur between sugars and other dietary macro-
nutrients, including fat and protein, to impact metabolic health
(Softic et al., 2018).
The most compelling clinical evidence that dietary sugar,
when consumed in amounts typical of Western diets, contributes
to adverse metabolic health comes from restriction studies,
particularly those performed in children and adolescents.
Some, but not all, studies showed that interventions aimed at
reducing SSB consumption reduce weight gain, adiposity, liver
fat, and indices of insulin resistance, depending on the study
population, the degree of sugar restriction and the duration of
the study (Ebbeling et al., 2012; de Ruyter et al., 2012; Schwarz
et al., 2017; Schwimmer et al., 2019).
Although the evidence that added sugars containing fructose
can negatively impact health indices is compelling, whether
these adverse effects are mediated exclusively through the ef-
fects of increased energy intake to enhance weight gain or
also through mechanisms independent of adiposity is less clear.
Complexity, cost, and ethical issues limit large-scale, long-term
dietary interventions that are needed to confirm effects on meta-
bolic and cardiovascular outcomes and to fully disentangle the
effects of added sugar on weight gain and adiposity from other
deleterious effects. Because of the difficulty in conducting
long-term dietary studies in ‘‘free-range’’ humans, studies in an-
imal models remain valuable. Non-human primate models with
physiologies that closely approximate our own may be an impor-
tant alternative model. Indeed, supplementation of the diets of
rhesus macaques with 300 kcal per day of fructose-sweetened
beverages, similar to that used in the Taskinen et al. study, for
up to 1 year produced many features of the metabolic syndrome,
including increased body weight, fat mass, insulin resistance,
dyslipidemia with hypertriglyceridemia and decreased HDL
cholesterol, and in some cases, overt diabetes (Bremer et al.,
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2011). Fructose supplementation in non-human primates can
induce dyslipidemia, steatosis, and the progression of NAFLD
(Butler et al., 2019, 2020; Cydylo et al., 2017; Kavanagh et al.,
2013) and may provide a more faithful model of the pathogenesis
of human cardiometabolic disease.
Although the literature largely focuses on the health risks of
increasing amounts of sugar, the mode of sugar exposure may
also affect its biological impact. In animal studies, sugar pro-
vided in liquid form may be more deleterious than when incorpo-
rated into solid food (Jang et al., 2020; Togo et al., 2019).
Additionally, sugar ingested as a single large daily bolus may
be more detrimental than frequent ingestion of smaller amounts
of fructose (Jang et al., 2020). These variables are not typically
assessed in current epidemiological studies and may contribute
to the variable associations of dietary sugar exposures with car-
diometabolic health.
Reduced physical activity is another environmental change
that is often invoked to explain our current obesity and diabetes
epidemics. Exercise acutely increases energy requirements and
mobilizes metabolic substrates to support muscle contraction.
Based on evidence that fructose provides some energetic
advantage when supplied during exercise, Tappy and Rosset
speculated that the adverse effects of fructose are magnified
in sedentary people (Tappy, 2018; Tappy and Rosset, 2017).
Spontaneous running attenuates sucrose-induced hypertrigly-
ceridemia in rats (Zavaroni et al., 1981). Modern hunter-gath-
erers of the Hadza tribe consume from 8% to 16% of their energy
intake as honey, which is largely fructose and glucose (Pontzer
et al., 2012). This is similar to the 50th and 95th percentiles of
sugar consumers, respectively, in the Western societies. Yet
Hadza foragers have a low prevalence of cardiovascular risk fac-
tors (Pontzer et al., 2012; Raichlen et al., 2017). Their high levels
of physical activity may mitigate the adverse effects of sugar
consumption.
Because of the growing concerns regarding the role of sugar
consumption in cardiometabolic disease, public health organiza-
tions have invested in measures aimed at reducing sugar con-
sumption, including dietary recommendations concerning
‘‘safe’’ limits for sugar consumption (Johnson et al., 2009; U.S.
Department of Agriculture and U.S. Department of and Health
and Human Services, 2020; World Health Organization 2015).
Given the lack of consensus regarding health risks and safe
thresholds, recommendations regarding sugar consumption
vary substantially. Aside from dietary recommendations, public
health studies have largely focused on behavioral interventions
to reduce SSB and sugar consumption in at-risk school-age chil-
dren with modest benefits (Rahman et al., 2018; Vercammen
et al., 2018). Interventions aimed at altering the physical or social
environment to reduce the selection of SSBs, such as warning la-
bels, in-store promotions of healthier beverages, price increases
on SSBs, government food benefits programs to disincentivize
SSB purchases, and increasing the availability of low-calorie
beverages in the home and community campaigns targeting
SSBs, have all shown some success (von Philipsborn et al.,
2020). Population-scale efforts to reduce SSB consumption
through SSB taxes appear effective (Fernandez and Raine,
2019; Redondo et al., 2018). However, whether any of these ef-
forts enhance health outcomes remains uncertain (Pfinder
et al., 2020).
Cell Metabolism 33, December 7, 2021 2331
 ll
INTESTINAL FRUCTOSE ABSORPTION
Following ingestion, fructose travels the gastrointestinal tract
to the small intestine where it is absorbed via transporters ex-
pressed on the brush border of intestinal epithelial cells.
GLUT5 (also known as Slc2a5) has marked specificity for fruc-
tose over glucose, although a wide range of Km for fructose (6
to 15 mM) has been reported depending on the assay system
(Burant et al., 1992; Douard and Ferraris, 2008). It is expressed
at high levels on the luminal membrane of the small intestine
with lesser expression on the basolateral membrane (Burant
et al., 1992; Davidson et al., 1992; Ferraris et al., 2018; Rand
et al., 1993). Its expression and activity are highest in the prox-
imal duodenum and decline along the length of the small intes-
tine (Rand et al., 1993). GLUT5 is essential for the intestinal
absorption of dietary fructose. GLUT5 knockout mice are
healthy and fertile on standard rodent chow diets, which
contain little or no fructose (Barone et al., 2009). However,
when exposed to diets containing fructose, these mice
develop a severe, morbid malabsorption syndrome character-
ized by diarrhea and intestinal distension (Barone et al., 2009)
(Table 1).
GLUT5 is a facilitative transporter; therefore, fructose trans-
port into the enterocyte is proportional to the concentration
gradient across the enterocyte luminal membrane. This con-
trasts with the intestinal glucose absorption, which is mediated
by the sodium-linked cotransporter, SGLT1, which can effi-
ciently pump glucose into the enterocyte against a concentration
gradient. This explains, in part, why intestinal glucose absorption
is faster and more complete than that of fructose (Cori, 1925).
Robust fructose phosphorylation within the enterocyte may be
important to maintain a steep luminal-enterocyte fructose
gradient to facilitate more complete fructose absorption (Patel
et al., 2015a). In contrast with glucose, which is nearly fully
absorbed within the small intestine, the intestinal capacity for
fructose transport can be saturated and some proportion of an
ingested fructose load may escape the small intestine and reach
the large intestine, where it is readily catabolized by gut micro-
biota (Zhao et al., 2020).
Although GLUT5 expression is responsible for intestinal fruc-
tose absorption, it is also expressed in other tissues and cell
types, including skeletal muscle, pre-adipocytes, the prostate
gland, spermatozoa, and erythrocytes (Burant et al., 1992;
Concha et al., 1997; Kayano et al., 1990; Reinicke et al., 2012).
However, the importance of fructose transport into these tissues
remains unclear.
Mechanisms mediating the efflux of both glucose and fructose
across the enterocyte basolateral membrane are less certain.
Both glucose and fructose efflux may be facilitated by GLUT2
(also known as Slc2a2), which is expressed at high levels on
basolateral membranes in enterocytes of the proximal small in-
testine (Davidson et al., 1992; Ferraris et al., 2018). GLUT2 is a
low-affinity, high-capacity facilitative transporter for both
glucose and fructose with similar affinities for both sugars (Km

11 mM) (Manolescu et al., 2007). However, glucose efflux
does not appear to be markedly impaired in either GLUT2-defi-
cient humans or mice (Santer et al., 2003; Stu €mpel et al.,
2001). As an alternative, exocytosis via a microsomal mem-
brane-based transport pathway has been proposed to play a
2332 Cell Metabolism 33, December 7, 2021
Review
major role in transcellular monosaccharide efflux (Stu €mpel
et al., 2001).
At birth, the expression of intestinal GLUT5 is negligible and in-
creases at weaning (Douard and Ferraris, 2008; Ferraris, 2001).
This induction is enhanced when such diets include fructose
(Ferraris, 2001). Fructose-mediated induction of intestinal
GLUT5 expression is dependent on intestinal fructose meta-
bolism (Patel et al., 2015b). The induction of intestinal GLUT5
expression in response to dietary fructose is mediated by carbo-
hydrate-responsive element-binding protein (ChREBP, also
known as Mlxipl), a carbohydrate-sensing transcription factor
expressed at high levels in the intestinal epithelia and other key
metabolic tissues (Kato et al., 2018; Kim et al., 2017; Oh et al.,
2018). A critical role for ChREBP in organismal fructose meta-
bolism was demonstrated by observations that in mice with
global or intestine-specific ChREBP knockout, exposure to
high-fructose diets failed to induce intestinal GLUT5 expression,
resulting in a malabsorption syndrome and morbidity within
1 week (Iizuka et al., 2004; Kato et al., 2018; Kim et al., 2017;
Oh et al., 2018). This morbidity is similar to the malabsorption
phenotype observed in GLUT5 knockout mice (Barone
et al., 2009).
Fructose absorption is highly variable in human children and
adults, depending on age, dietary sugar exposure, and likely
other unidentified genetic, dietary, and environmental factors
(reviewed in Ferraris et al., 2018). Fruit juices, such as apple juice,
which contain large amounts of fructose, are commonly
consumed in large quantities by young children and may cause
nonspecific gastrointestinal symptoms that resolve with reduc-
tions in juice consumption (Ushijima et al., 1995). Fructose
malabsorption can be measured via detection of colonic flora-
derived gases, such as hydrogen or methane, after ingestion of
an oral fructose load (Rao et al., 2007). Some, but not all, studies
using such methods find associations between fructose malab-
sorption and functional gastrointestinal symptoms (Fernández-
Bañares et al., 1993; Melchior et al., 2014). Reducing the
consumption of dietary fructose, in addition to other highly
fermentable but poorly absorbed carbohydrates and polyols,
may be useful to treat a range of gastrointestinal symptoms
and conditions (Gibson and Shepherd, 2005).
Although genetic ablation of GLUT5 causes fructose malab-
sorption in mice, fructose malabsorption in humans is not neces-
sarily associated with reduced intestinal GLUT5 expression
(Wasserman et al., 1996). Thioredoxin-interacting protein
(TXNIP) is another ChREBP-regulated, fructose-induced protein
that is expressed in key metabolic tissues, including the liver and
intestine (Dotimas et al., 2016; Iizuka et al., 2004). TXNIP facili-
tates the localization of facilitative hexose transporters to plasma
membranes, including localization of GLUT5 to enterocyte
luminal membranes (Shah et al., 2020). Thus, factors regulating
proper GLUT5 localization and function, in addition to its expres-
sion, may also be important determinants of dietary fructose ab-
sorption.
It is not known whether natural variation in intestinal fructose
absorption or hepatic fructose metabolism contributes to fruc-
tose-induced cardiometabolic disease. Walker and colleagues
noted that African Americans had higher rates of fructose
malabsorption associated with lower liver fat compared with His-
panic controls and that within African Americans, fructose
 Review
Table 1. Metabolic effects resulting from genetic manipulation of fructolytic enzymes and related factors in animals challenged with high dietary fructose
Gene target Intervention Phenotype References
GLUT5 (SLC2A5) global KO malabsorption syndrome associated with Barone et al., 2009
intestinal distension, diarrhea, and marked
weight loss within 1 week
KHKa/c global KO reduced weight gain and adiposity; reduced Diggle et al., 2009;
glycemia and insulin; reduced hepatic Ishimoto et al., 2012
steatosis; mildly reduced ad libitum
fructose consumption; increased urinary
fructose excretion
liver KD – ASO reduced weight gain; reduced hepatic Softic et al., 2018
steatosis; improved glucose tolerance
liver KO reduced weight gain; reduced hepatic Andres-Hernando et al., 2020b
steatosis; reduced insulin; increased
urinary fructose excretion
intestine KO reduced ad libitum fructose consumption; Andres-Hernando et al., 2020b
despite reduced fructose consumption,
persistent increases in body weight and
hepatic steatosis
KHKa global KO increased weight gain and adiposity; (Diggle et al., 2010);
increased insulin and hepatic steatosis Ishimoto et al., 2012
KHKc intestine KO increased portal fructose levels; increased Jang et al., 2020
fructose delivery to microbiota; increased
hepatic DNL; increased circulating
triglycerides and hepatic steatosis
intestine OX reduced portal fructose levels; reduced Jang et al., 2020
Cell Metabolism 33, December 7, 2021 2333

DNL, reduced ad libitum fructose

consumption
ALDOB global KO steatosis on fructose-free diets and rapid Lanaspa et al., 2018a;
development of severe steatosis and Oppelt et al., 2015
inflammation with fructose exposure;
morbidity and mortality within 1 week of
fructose exposure; rescue with
pharmacological inhibition of KHK
TKFC global KO – Liu et al., 2020
(Continued on next page)

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2334 Cell Metabolism 33, December 7, 2021

ll
Table 1. Continued
Gene target Intervention Phenotype References
ChREBP (MLXIPL) global KO weight loss, hypothermia, and severe Iizuka et al., 2004
morbidity and mortality within 1 week of
fructose challenge; increased hepatic
glycogen and hexose phosphates
global KO prevents fructose-induced expression of Kim et al., 2016
the hepatic fructolytic program; reduced
endogenous glucose production; impaired
glycogenolysis; increased hepatic hexose
phosphates.
global KO fructose and sucrose malabsorption Kato et al., 2018;
associated with diarrhea, intestinal Oh et al., 2018
distension, and alterations in microbiome
global KO weight loss; liver inflammation (Zhang et al., 2017)
liver KD – ASO (rat) reduced circulating triglycerides; enhanced Erion et al., 2013
peripheral insulin sensitivity; reduced DNL;
increased hepatic glycogen; mild
transaminitis without liver inflammation
liver KO reduced weight gain and adiposity; reduced Kim et al., 2017
circulating insulin; reduced DNL; increased
hepatic glycogen; preserved glycerol
tolerance; mild transaminitis without liver
inflammation
liver KO marked hepatic glycogen accumulation (Shi et al., 2020)
associated with transaminitis without liver
inflammation
intestine KO weight loss with fructose malabsorption Kim et al., 2017
and intestinal distension associated with
severe morbidity and mortality within
1 week of fructose challenge
KO, knockout; KD, knockdown; OX, overexpression. All genetic interventions were performed in mice unless otherwise specified.

Review

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malabsorption correlated inversely with liver fat (Walker et al.,
2012). Another small study indicated that children with NAFLD
may have enhanced fructose absorption compared with lean con-
trols and that children with either NAFLD or obesity may have
enhanced fructose metabolism compared with their lean counter-
parts (Sullivan et al., 2015). Intriguingly, recent work has shown
that GLUT5 expression and glucose production are increased
from intestinal stem-cell-derived enteroids generated from intes-
tinal biopsies obtained from patients who had obesity compared
with lean controls (Hasan et al., 2021). Although these studies
suggest the possibility that innate differences in intestinal function
might contribute to fructose-related metabolic phenotypes, it re-
mains unclear whether these observed differences might be
causes or consequences of obesity and NAFLD.
ORGANISMAL FRUCTOSE METABOLISM AND THE
IMPORTANCE OF THE INTESTINE AND LIVER
The innate differences in mammalian glucose versus fructose
metabolism are reflected in the marked differences in their circu-
lating blood levels. Whereas normal fasting glucose concentra-
tions in peripheral blood are
5 mM, fructose circulates at less
than
0.02 mM in fasted conditions (Chen et al., 2020; Francey
et al., 2019). The ingestion of a large, isolated glucose load as
performed during a glucose tolerance test produces peripheral
glycemia of
7.5 mM in healthy individuals. In contrast, an equiv-
alently large oral fructose load transiently increases the periph-
eral circulating fructose levels with peaks rarely exceeding

1 mM. This is followed by a rapid return to low micromolar
levels within hours. The absence of a comparatively large in-
crease in the peripheral circulating fructose following ingestion
of a large oral fructose load illustrates the gut’s ability to metab-
olize most of the orally ingested fructose. Relatively little escapes
to the peripheral circulation (Figure 1). Using a sophisticated
dual-tracer approach in humans, Fancey et al. recently demon-
strated that after ingesting a drink containing 30 g fructose and
30 g glucose, only 15% of the fructose escaped the first-pass
gut metabolism (Francey et al., 2019).
For the last half century, conventional wisdom suggested that
the liver accounted for most of the fructose clearance by the gut.
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Figure 1. Organismal fructose metabolism
and first-pass extraction in the gut
Following ingestion of a large oral fructose load,
fructose is absorbed into intestinal epithelial enter-
ocytes. A portion of this fructose is phosphorylated
by KHK within the enterocyte and is converted to
glucose, lactate, glycerate, and other organic acids,
which travel via the portal vein to the liver. Portal
fructose concentrations can transiently reach con-
centrations as high as
1 mM. Fructose reaching
the liver is efficiently extracted by hepatocytes and
phosphorylated by KHK, where it can be used for
glucose production, lipogenesis, glycogen synthe-
sis, and energetic purposes. Peripheral blood
fructose concentrations transiently peak at levels

10-fold lower than peak portal levels.
This perspective originated from classical
studies conducted by Denker et al., Holds-
worth et al., and others that measured
1
to 2 mM fructose in the portal vein of human study participants
following oral administration of fructose (Cook, 1969; Dencker
et al., 1972; Holdsworth and Dawson, 1965). Cotemporaneous
work in baboons demonstrated that the gastric installation of 2
g/kg body mass sucrose achieved fructose concentrations of
2 mM in the portal vein, whereas simultaneous measurements
in femoral arterial blood transiently peaked at 0.7 mM (Crossley
and Macdonald, 1970). Similar results were obtained in other an-
imals (Topping and Mayes, 1971). The large decrement in fruc-
tose concentrations from portal blood to peripheral arterial blood
speaks to the efficiency of hepatic fructose extraction confirmed
in the liver perfusion experiments (Mayes, 1993).
Recent work in mice conducted by Jang et al. refocused atten-
tion on the relative importance of liver versus intestinal fructose
metabolism (Jang et al., 2018). Using a stable isotope approach,
Jang and colleagues reported that in mice gavaged with fructose
at a dose of 0.5 g/kg body mass,
90% of the absorbed fructose
was metabolized within the small intestine and a relatively little
amount reached the liver. Most of the fructose metabolized
within the intestine appeared in the portal vein as glucose or
other fructose-derived metabolic products, including lactate,
alanine, glycerate, and other organic acids. The small intestine
expresses the full complement of gluconeogenic enzymes and
is capable of robust conversion of ingested fructose into circu-
lating glucose (Bismut et al., 1993; Ginsburg and Hers, 1960;
Jang et al., 2018). Although studies show that the robust conver-
sion of fructose to glucose is readily detectable in the intestines
of many species, earlier studies suggested that this did not occur
in humans (Cook, 1969; Holdsworth and Dawson, 1965). Howev-
er, reexamination of isotopic tracer data in studies performed in
human children is consistent with extensive conversion of in-
gested fructose to glucose in human intestines as well (Bismut
et al., 1993; Gopher et al., 1990).
Whether intestinal fructose metabolism is dominant over liver
fructose metabolism in animals other than mice is less clear.
The relative importance of intestinal fructose metabolism may
be different among species (Ginsburg and Hers, 1960). The in-
testinal GLUT5 expression is markedly higher in rats and humans
compared with mice (Kim et al., 2007). These differences may
contribute to observations that portal fructose levels peaked
Cell Metabolism 33, December 7, 2021 2335
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Review

Figure 2. Fructolysis and associated biochemistry

Fructose is transported into enterocytes and hepatocytes via GLUT5 and GLUT2, respectively. Upon entering the cells, fructose is phosphorylated by KHK to
F1P. Energy depletion resulting from robust fructose phosphorylation leads to activation of AMPD2 and uric acid production. F1P is cleaved by ALDOB to DHAP
and GA. GA is phosphorylated by triose-kinase (TKFC) to GA3P. Both DHAP and GA3P mix with triose-phosphates common to the glycolytic and gluconeogenic
carbon pools. In hepatocytes, F1P allosterically inhibits PGYL to enhance glycogen synthesis and disrupts the interaction between GCK and GCKR, allowing
GCK to translocate from the nucleus to the cytoplasm and catalyze phosphorylation of glucose, further increasing the hexose- and triose-phosphate carbon
pools. Fructose-derived substrate has numerous fates, including use in de novo lipogenesis (DNL), both through direct and indirect pathways via microbiome-
derived acetate. KHK, ketohexokinase; AMPD3, adenosine deaminase; IMP, inosine monophosphate; ALDOB, aldolase B; TKFC, triokinase and FMN cyclase;
GA, glyceraldehyde; DHAP, dihydroxyacetone phosphate; GA3P, glyceraldehyde 3-phosphate; PYGL, glycogen phosphorylase L; GYS2, glycogen synthase 2;
PKLR, pyruvate kinase, liver and red blood cell; PEP, phosphoenolpyruvate.

at
0.3 mM in mice after fructose gavage, whereas peak portal
fructose concentrations were 3- to 5-fold higher in other animals,
including humans (Crossley and Macdonald, 1970; Holdsworth
and Dawson, 1965; Topping and Mayes, 1971). Additional
detailed studies are required to clarify the importance of intesti-
nal versus liver fructose metabolism in larger animals, including
humans.
Nevertheless, these studies led to a novel and important
concept that intestinal fructose metabolism might shield the liver
from excessive exposure to dietary fructose, where its meta-
bolism may be particularly deleterious (Jang et al., 2018). This
issue will be explored in more detail later in this review.
CELLULAR AND INTERMEDIARY FRUCTOSE
METABOLISM
Fructose transport across cell membranes relies on facilitative
hexose carriers, such as GLUT5, in enterocytes, as there is no
known active transporter. In the liver, the other major site of fruc-
tose metabolism, GLUT5 is not expressed at high levels, and
GLUT2 is likely the major membrane transporter for both glucose
and fructose. GLUT8 (also known as Slc2a8), which also has af-
finity for fructose, has been reported to contribute to fructose
transport in both enterocytes and hepatocytes (DeBosch et al.,
2012, 2014; Schmidt et al., 2009). However, it predominately lo-
calizes to endosomal and lysosomal compartments rather than
the cell surface (Alexander et al., 2020; Schmidt et al., 2009).
Upon transport into the cell, fructose is metabolized by a
cascade of three ‘‘fructolytic’’ enzymes, originally delineated
by Henri Hers during his graduate studies (Hers, 1957) (Figure 2).
These fructolytic enzymes efficiently convert the hexose fructose
into triose-phosphates, which are incorporated into the cellular
pools of triose-phosphates generated via glycolysis and gluco-
neogenesis. The first step in fructolysis is the rapid and irrevers-
ible phosphorylation of fructose to fructose-1-phosphate (F1P)
catalyzed by ketohexokinase (KHK, also known as fructokinase).
This metabolite is specific to the fructolytic pathway and is not
shared with glycolysis or gluconeogenesis. Compared with
glucose, fructose is a poor substrate for hexokinases I, II, and
III (Km glucose < 0.1 mM; Km fructose
1–10 mM) (Diggle
et al., 2009; Grossbard and Schimke, 1966; Middleton, 1990).
At typical circulating concentrations, glucose potently inhibits
fructose metabolism by these hexokinases (Diggle et al., 2009;
Froesch and Ginsberg, 1962). This is particularly true for

2336 Cell Metabolism 33, December 7, 2021


Review
glucokinase (GCK), the predominate hexokinase in hepatocytes
and pancreatic beta cells (Km for glucose
5 mM, Km fructose >
100 mM) (Diggle et al., 2009; Froesch and Ginsberg, 1962; Mid-
dleton, 1990; Pollard-Knight and Cornish-Bowden, 1982).
Unlike many other hexokinases, KHK is inhibited neither allo-
sterically by ATP nor by other signals of cellular energy suffi-
ciency, nor by its immediate product. The capacity of KHK to
phosphorylate fructose is comparable with the capacity of
GCK to phosphorylate glucose in rodent livers and 10-fold higher
in human livers (Heinz et al., 1968). Moreover, whereas KHK is
constitutively active, hepatic GCK is sequestered in the nucleus
in an inhibited state by glucokinase regulatory protein (GCKR)
(Agius, 2008; Niculescu et al., 1997). The sequestration and inhi-
bition of GCK by GCKR and the stabilization of this inhibited state
by the glycolytic intermediate fructose-6-phosphate (F6P) limit
the net hepatic glucose uptake and hepatic glucose clearance
after oral ingestion of an isolated glucose load (Agius, 2008;
Pollard-Knight and Cornish-Bowden, 1982; Van Schaftingen,
1994). In contrast, because of the low Km and high activity of
KHK for fructose and the lack of regulation of its activity, the ma-
jority of fructose that arrives at the liver via the portal circulation is
readily extracted and little reaches the systemic circulation.
The consumption of ATP by KHK-mediated fructose phos-
phorylation can be so robust that intravenous infusions of large
fructose loads cause an acute decline in the hepatocellular
ATP-to-AMP ratio and a marked decline in free phosphate as it
is sequestered in F1P (Bode et al., 1973; Mayes, 1993). F1P
can rapidly accumulate to millimolar concentrations in hepato-
cytes (Woods et al., 1970). These changes in F1P levels and
cellular energy status are detectable by non-invasive 31P mag-
netic resonance spectroscopy in human livers (Oberhaensli
et al., 1986). Following fructose infusion, hexose-phosphate
levels increased 7-fold within minutes and steadily declined to
basal levels after
20 min. Hepatic ATP levels declined by
more than 80% within minutes and recovered to only
50% of
basal levels after 1 h (Oberhaensli et al., 1986). Whereas intrave-
nous infusions of fructose can cause acute and profound
changes in hepatic metabolite levels and energy status, oral fruc-
tose administration results in more modest changes, likely due to
the substantial metabolism of fructose within the intestine (Nie-
woehner et al., 1984). Nevertheless, a recent NMR study indi-
cates that ATP depletion can be detected in the human liver
following an oral 75 g fructose challenge, indicating that hepatic
fructose metabolism in humans is substantial (Bawden
et al., 2016).
Phosphate potently inhibits the enzyme AMP deaminase
(Ampd2), which catalyzes the rate-limiting step in purine degra-
dation and uric acid production (van den Berghe et al., 1977).
Thus, the decline in free phosphate resulting from fructose phos-
phorylation potently activates Ampd and uric acid production.
Fructose may also stimulate purine synthesis (Raivio and
Becker, 1975). The crystallization of uric acid in joints causes
the painful rheumatological condition of gout. Thus, fructose-
induced uric acid production may contribute to the association
between SSB consumption and a risk of gout, but it also likely
underlies the association between hyperuricemia and cardiome-
tabolic disease (Jamnik et al., 2016; Yoo et al., 2005).
Although the committed phosphorylation steps in glucose and
fructose metabolism are catalyzed by distinct enzymes, the he-
ll
patic metabolism of glucose and fructose is not entirely indepen-
dent of each other. F1P, the product of KHK-mediated fructose
phosphorylation, potently relieves the inhibitory effect of GCKR
on GK, permitting its translocation to the cytosol and enhancing
hepatic glucose uptake and metabolism (Niculescu et al., 1997).
Thus, the ‘‘catalytic’’ amounts of fructose can markedly enhance
hepatic glucose (Petersen et al., 2001; Van Schaftingen, 1994).
F1P may also activate pyruvate kinase, the terminal step in
glycolysis (Eggleston and Woods, 1970), and can inhibit
glycogen phosphorylase (Kaufmann and Froesch, 1973; Thur-
ston et al., 1974; Van Den Berghe et al., 1973). Through these
F1P-mediated activities, the fructose contained in dietary sugars
as part of a meal may act as a signal to modulate hepatic fuel
metabolism.
Recent work has firmly established additional roles for F1P as
a key signaling molecule. Taylor et al. recently demonstrated that
F1P can bind the M2 isoform of pyruvate kinase (PKM2) and limit
the formation of highly active PKM2 tetramers (Taylor et al.,
2021). PKM2 monomers and dimers are capable of binding
and transactivating HIF-1a, a transcription factor essential for
cellular adaptation to hypoxia (Luo et al., 2011). This protection
against hypoxia increases enterocyte cell survival, leads to elon-
gation of the intestinal villus, and increases absorptive capacity.
Thus, fructose feeding, by increasing the intestinal absorptive
surface, may enhance energy harvest and potentially contribute
to obesity in calorie-rich environments.
Following fructose phosphorylation, F1P is cleaved by
aldolase B (ALDOB) to dihydroxyacetone phosphate (DHAP)
and glyceraldehyde. Glyceraldehyde is then phosphorylated by
a triokinase (TKFC, triokinase and FMN cyclase) to glyceralde-
hyde 3-phosphate (G3P). DHAP and G3P then enter the glyco-
lytic/gluconeogenic carbon pools.
Although cellular and organismal fuel status does not regulate
fructolytic flux, fuel status does impact the fate of fructose-
derived triose-phosphates that enter the central carbon pools
(Mayes, 1993). For instance, in fasted or starved animals, when
PFK activity is limited by decreased fructose 2,6-bisphosphate
levels, fructose-derived triose-phosphates will be routed toward
glucose production (Exton and Park, 1967; Exton et al., 1966). In
contrast, in fed animals, fructose-derived triose-phosphates
may be preferentially metabolized to pyruvate and released as
lactate or used as substrate for lipogenesis (Topping and Mayes,
1976). Nutrients co-ingested with fructose may also affect its
metabolic fate. For instance, insulin that is secreted when
glucose and fructose are ingested together may be important
for the full effects of fructose to stimulate glycogen synthesis
(Topping and Mayes, 1976). Thus, the fate and effects of in-
gested fructose on systemic fuel homeostasis depend on sys-
temic fuel status.
KETOHEXOKINASE: GENETIC LESSONS IN HUMANS
AND MICE AND THERAPEUTIC IMPLICATIONS
KHK catalyzes the committed step in fructose metabolism,
phosphorylating fructose to F1P. Loss-of-function KHK muta-
tions in humans produce the condition called benign essential
fructosuria (Asipu et al., 2003; Steinmann et al., 2019). A large
and persistent increase in circulating fructose is produced
when people with this condition consume foods containing
Cell Metabolism 33, December 7, 2021 2337
 ll
fructose (Laron, 1961; Steinmann et al., 1975). As the name of the
condition suggests, in people with this condition,
20% of the
fructose is excreted in the urine following an oral or intravenous
fructose load (Laron, 1961; Steinmann et al., 1975). The
remainder is presumably phosphorylated and cleared by canon-
ical hexokinases, possibly in the adipose tissue and the skeletal
muscle (Froesch and Ginsberg, 1962). Prior to the widespread
use of glucose oxidase in assays to measure glucose levels in
blood and urine samples, cases of benign essential fructosuria
came to clinical attention when the use of Benedict’s reagent
incidentally detected high levels of reducing sugars in the urine,
and glucose was subsequently excluded with more specific
testing. Because Benedict’s reagent is no longer in regular
use, and because there are no known or reported adverse
clinical consequences associated with loss of KHK activity, indi-
viduals with this condition likely go undetected. Although this
condition appears to be uncommon, review of data from exome
sequencing projects indicates that there is no strong selection
against missense or loss-of-function variants in the KHK gene
in human populations (Johnston et al., 2021).
Despite increased circulating fructose in people with benign
essential fructosuria, there is no increase in blood insulin and
there are no reports of diabetic complications or increases in
%HbA1c (Petersen et al., 1992; Steinmann et al., 1975). The
absence of pathology indicates that fructose metabolism via
KHK is essential for fructose-induced metabolic disease. This
hypothesis is further supported by a mouse with global inactiva-
tion of KHK (Ishimoto et al., 2012). Although KHK knockout mice
showed a decreased preference for fructose-supplemented
drinking water compared with controls, when matched for total
energy and fructose intake, KHK knockout mice were fully pro-
tected from fructose-induced increases in body weight, fat
mass, serum insulin, and hepatic steatosis (Ishimoto et al.,
2012). Thus, fructose metabolism via KHK is essential for fruc-
tose-induced metabolic disease.
KHK is expressed as two distinct isoforms from a single gene
(Hayward and Bonthron, 1998). Mutually exclusive splicing of
exons 3a and 3c in KHK pre-mRNA produces distinct mRNAs
that encode KHKa and KHKc protein isoforms, respectively.
The Km of KHKc for fructose is
0.5 mM, whereas the Km of
KHKa for fructose is more than an order of magnitude higher
(Diggle et al., 2009). KHKa is expressed at low levels ubiqui-
tously. In contrast, KHKc is expressed at high levels selectively
in key metabolic tissues, including the liver, small intestine, and
kidney (Diggle et al., 2009). In addition to knockout mice in which
both KHK isoforms were globally ablated, Ishimoto and col-
leagues generated a mouse in which the KHKa isoform was
selectively deleted. The selective ablation of KHKa exacerbated
fructose-induced disease, indicating that, despite its low levels,
KHKa likely does contribute to systemic fructose metabolism
(Ishimoto et al., 2012). In contrast, selective deletion of KHKc re-
vealed that it is primarily responsible for fructose-induced meta-
bolic disease. This conclusion is further supported by recent
work conducted by Nikolaou et al. on identifying the antagonistic
actions of RNA-binding proteins A1CF and hnRNPH1/2 that
regulate KHKa/c splicing (Nikolaou et al., 2019). A1CF knockout
reduces the expression of the KHKc isoform and protects mice
from fructose-induced metabolic disease (Nikolaou et al.,
2019). Regulated splicing of KHK and altered fructose meta-
2338 Cell Metabolism 33, December 7, 2021
Review
bolism have also been implicated in other diseases, including
hepatocellular carcinoma and heart failure (Li et al., 2016; Mirt-
schink et al., 2015).
Together, these studies indicate that fructose metabolism in a
tissue that expresses the KHKc isoform is critical for fructose-
induced metabolic disease. As previously noted, KHKc is ex-
pressed in both the intestine and the liver and the intestine is
capable of substantial fructose metabolism. Knockout of intesti-
nal KHK exacerbates fructose-induced metabolic disease,
whereas liver-specific knockout or knockdown of KHK protects
against fructose-induced metabolic disease (Andres-Hernando
et al., 2020b; Jang et al., 2020; Softic et al., 2018). These results
support the hypothesis that intestinal fructose metabolism may
shield the liver from fructose exposure, where its metabolism
may be particularly harmful. Mechanisms by which hepatic
metabolism may contribute to metabolic disease will be ad-
dressed in the subsequent sections of this review.
Given the evidence that fructose metabolism via KHK is
required for fructose-induced metabolic disease and that inacti-
vating mutations in KHK are not associated with adverse clinical
effects in humans, targeting the inhibition of KHK as a therapeu-
tic strategy seems to hold great promise. Recently, pharmaceu-
tical companies have initiated programs aimed at developing
novel potent and specific KHK inhibitors, which are beginning
to provide data in pre-clinical and early-phase clinical trials (Fu-
tatsugi et al., 2020; Gutierrez et al., 2021; Kazierad et al., 2021).
Pre-clinical studies in rats demonstrated that the KHK inhibitor
PF-06835919 dose-dependently attenuated hyperinsulinemia,
hypertriglyceridemia, and steatosis provoked by a high-fructose
diet. These protective effects were associated with marked in-
creases in circulating fructose and fructosuria and were accom-
panied by an attenuated induction of hepatic ChREBP activity
and DNL (Gutierrez et al., 2021). Importantly, PF-06835919
also enhanced metabolic indices in rats on an ‘‘American diet,’’
indicating that KHK inhibition may be healthful outside of
extreme fructose exposures. To this end, a randomized, dou-
ble-blind, placebo-controlled Phase 2a study (NCT03256526)
in adults with baseline NAFLD, PF-06835919, produced an
18.7% reduction in liver fat after 6 weeks of treatment with a
300 mg but not a 75 mg daily dose (Kazierad et al., 2021). Treat-
ment with the KHK inhibitor resulted in increased fructosuria
consistent with robust KHK inhibition in vivo. This was also
associated with improvements in inflammatory markers and in-
creases in circulating adiponectin levels. The drug was well toler-
ated. This short-term study provides optimism that inhibiting
fructose metabolism may provide a new therapeutic strategy
for treating cardiometabolic disease soon.
ADDITIONAL FRUCTOLYTIC ENZYMES: GENETIC
LESSONS IN HUMANS AND MICE
Whereas the global KHK loss-of-function mutations are benign,
the loss-of-function mutations in Aldob, the second step in fruc-
tolysis, cause hereditary fructose intolerance (HFI), an autosomal
recessive Mendelian disorder with a significant morbidity (Ali
et al., 1998; Hers and Joassin, 1961; Perheentupa et al., 1972).
Individuals with this condition tolerate carbohydrates containing
glucose or galactose, whereas ingestion of sucrose or fructose
triggers abdominal pain, nausea, and vomiting accompanied

Review
by acute hypoglycemia. This condition often presents in infants
as a failure to thrive accompanied by liver toxicity after weaning
from breast milk or the introduction of a fructose-containing for-
mula. Aversion to sweet-tasting foods is also common (Cham-
bers and Pratt, 1956). Persistent exposure to fructose ultimately
leads to liver and kidney failure and, ultimately, death (Baerlocher
et al., 1978). Similar morbidity and mortality can also be pro-
voked by administration of sorbitol, a metabolite that can be
used to produce fructose endogenously via the polyol pathway
(Ali et al., 1998). People with this condition often learn to avoid
all dietary sources of fructose, and are often devoid of dental
caries, supporting evidence that dietary sucrose is a major
contributor to poor dental health (Ali et al., 1998; Marthaler and
Froesch, 1967; Touger-Decker and van Loveren, 2003). Elimina-
tion of all dietary sucrose, fructose, and sorbitol is the mainstay
of treatment and improved health can be observed within days of
fructose restriction (Mock et al., 1983; Steinmann et al., 2019).
Properly treated, HFI patients may experience normal health,
growth, and lifespan.
Lean and healthy adults with HFI on low-fructose diets have
increased intrahepatic triglyceride and glucose intolerance (Si-
mons et al., 2019). This speaks to the importance of F1P as a
metabolic signal and indicates that increased fructolytic flux
per se is not necessary for the pathogenesis of these features.
Additional support for the importance of F1P as a signaling mole-
cule comes from recent studies in adults heterozygous for HFI
(hHFI) and controls (Debray et al., 2021). Whereas a high-fruc-
tose diet increased fasting uric acid and insulin resistance simi-
larly in both hHFI patients and controls, in the post-prandial
condition, plasma uric acid and liver insulin resistance increased
only in the hHFI patients (Debray et al., 2021).
Fructose toxicity in HFI is attributed, in part, to the deleterious
effect of the marked and prolonged accumulation of F1P in he-
patocytes, enterocytes, and epithelial cells of the proximal tu-
bule (Oberhaensli et al., 1987; Steinmann et al., 2019; Van Den
Berghe et al. 1973). ATP depletion and uric acid production are
also posited to contribute to toxicity in the affected cell types
(Steinmann et al., 2019; Van Den Berghe et al. 1973). Hypoglyce-
mia that occurs acutely after fructose consumption in HFI may be
due to the effects of F1P glucokinase activation and also the ef-
fects of very high levels of F1P on inhibiting glycogenolysis and
gluconeogenesis (Rambaud et al., 1973; Steinmann et al.,
2019; Van Den Berghe et al. 1973). This may be mediated by
an effect of F1P to inhibit glycogen phosphorylase (Van Den
Berghe et al., 1973).
Although fructose metabolism in the liver, intestine, and kidney
is greatly impaired in HFI, less than 20% of the fructose load is
recovered in the urine in these patients, indicating that the major-
ity of the fructose is metabolized in other tissues (Landau et al.,
1971). Adipose tissue metabolism of fructose to fructose-6-
phosphate by hexokinase II may be the major mode of fructose
metabolism in this condition, as may also be the case in benign
essential fructosuria (Froesch and Ginsberg, 1962).
The molecular physiology of HFI has been confirmed in a
mouse model with global knockout of Aldob (Oppelt et al.,
2015). This model recapitulates features observed in human
patients, including morbidity and mortality, when exposed to
high-fructose diets. On a fructose-free diet, these mice develop
steatosis, as is the case for humans with HFI. This may be, in
ll
part, due to signaling effects of increased F1P generated from
endogenously produced fructose (Oppelt et al., 2015). The in-
crease in steatosis in Aldob knockout mice can be reversed by
inhibiting KHK, which further supports the hypothesis that F1P
is a critical signaling molecule in the pathogenesis of this condi-
tion (Lanaspa et al., 2018a).
As the adverse effects of HFI depend on fructolytic flux, the in-
hibition of KHK could potentially be therapeutic for HFI as it is for
other forms of fructose-induced disease. In support of this
strategy, Lanaspa and colleagues noted that Osthole, a plant-
derived coumarinic derivative with pleiotropic biological effects,
including KHK inhibition, is able to prevent adverse metabolic
symptoms in Aldob knockout mice (Lanaspa et al., 2018a; Le
et al., 2016). These results provide hope that KHK inhibitors
may be useful to markedly expand food options in people with
this condition and warrant trials with newly developed potent
and specific KHK inhibitors.
The Aldob cleavage reaction generates two metabolites from
F1P—DHAP and glyceraldehyde. DHAP requires no further
metabolism to join the glycolytic triose-phosphate pool. Howev-
er, glyceraldehyde, a potentially reactive and toxic metabolite, is
phosphorylated by Tkfc to the glycolytic intermediate glyceral-
dehyde-3-phosphate, completing the final step in fructolysis.
Tkfc has been studied less intensively than the preceding two
steps, in part, because there are no known clinical conditions
associated with mutations in this enzyme. Mice with liver-spe-
cific or global Tkfc knockdown demonstrate liver inflammation
and evidence of fructose malabsorption when challenged with
high-fructose diets, potentially related to toxicity of fructose-
derived glyceraldehyde (Liu et al., 2020; Sillero et al., 1969).
These mice demonstrated increased glycerate and serine syn-
thesis, suggesting metabolism of glyceraldehyde via aldehyde
dehydrogenase (Sillero et al., 1969). The recent observation in
mice that a substantial fraction of ingested fructose is exported
from enterocytes into portal blood as glycerate suggests that
Tkfc activity may be limiting for fructolysis in some conditions
(Jang et al., 2018).
MOLECULAR MEDIATORS OF FRUCTOSE ON LIPID
HOMEOSTASIS
As previously noted, the potential deleterious effects of fructose
on metabolism were initially recognized through its adverse ef-
fects on lipid homeostasis. This included the ability of extremely
high fructose exposures far exceeding those of typical Western
diets to provoke fasting hypertriglyceridemia and steatosis and
to enhance prandial lipemia within a matter of days. These
changes in liver and circulating triglyceride levels are consis-
tently associated with increased hepatic DNL—the biochemical
process by which new fatty acids are synthesized from precursor
molecules (Geidl-Flueck et al., 2021; Lê et al., 2009; Wakil et al.,
1983). Indeed, fructose ingestion can increase the amount of
newly synthesized fatty acids found within circulating triglyceride
in hours (Hudgins et al., 2011). Moreover, newly synthesized fatty
acids are increasingly recognized as major contributors to he-
patic fat accumulation associated with obesity and NAFLD (Don-
nelly et al., 2005; Lambert et al., 2014; Smith et al., 2020).
Fructose may facilitate DNL through multiple mechanisms
(Figure 3). Fructose-derived metabolites, such as F1P, act as
Cell Metabolism 33, December 7, 2021 2339
 ll
Figure 3. Fructose activates metabolic gene expression
Fructose-derived metabolites act as signaling molecules to activate metabolic
transcriptional programs. F1P derived from fructose metabolism activates
GCK, and the combination of fructose- and glucose-derived hexose phos-
phates activates ChREBP, which coordinately regulates enzymes involved in
fructolysis, glycolysis, glucose production, lipogenesis, and VLDL packaging
and export. Fructose-derived metabolites may also activate SREBP1c. Both
ChREBP and SREBP1c are coactivated by PGC1b to further coordinate
and enhance transcription of metabolic programs. ACLY, ATP citrate lyase;
ACACA, acetyl-CoA carboxylase a; FASN, fatty acid synthase; GPAT, glycerol-
3-phosphate acyltransferases; Agpat, acylglycerol-3-phosphate acyltransfer-
ase; DGAT, diacylglycerol acyltransferase; MTTP, microsomal triglyceride
transfer protein; TM6sf2, transmembrane 6 superfamily, member 2; TAG, tri-
acylglycerol; VLDL, very-low-density lipoprotein.
signaling molecules to promote DNL (Kim et al., 2016). As noted
earlier, this is supported by evidence in patients and animal
models of HFI, where increased F1P but decreased fructolytic
flux are associated with increased steatosis. Nevertheless,
increased fructolytic flux may also provide substrate and
reducing equivalents to support fatty acid synthesis (Wakil
et al., 1983). Additionally, uric acid generated as a result of rapid
fructose catabolism has been suggested to promote DNL (La-
naspa et al., 2012).
The predominant mechanism by which fructose induces DNL
in the liver is through its effects on increasing hepatocellular F1P,
which causes the dissociation of GCK from its inhibitory binding
2340 Cell Metabolism 33, December 7, 2021
Review
partner, GCKR (Agius, 2008; Van Schaftingen, 1994). This serves
to increase glycolytic flux and increases the concentration of
hexose- and triose-phosphates within the hepatocyte (Kim
et al., 2016). One or more of these glucose metabolites activates
ChREBP, leading to coordinate upregulation of the full comple-
ment of enzymes required for DNL (Dentin et al., 2004; Iizuka
et al., 2004; Katz et al., 2021; Kim et al., 2016). Increased glyco-
lytic flux via activation of GCK also provides additional substrate
and reducing equivalents, supporting both DNL and glycogen
synthesis.
ChREBP is an evolutionarily conserved, carbohydrate-sensing
transcription factor that is highly expressed in key metabolic cell
types, including enterocytes, hepatocytes, adipocytes, pancre-
atic beta cells, and proximal tubule cells of the kidney (Iizuka
et al., 2004; Katz et al., 2021; Uyeda and Repa, 2006). ChREBP
is required for carbohydrate-mediated induction of glycolytic
and lipogenic enzymes in the liver (Iizuka et al., 2004). It also
transactivates the expression of the complement of fructolytic
enzymes (Iizuka et al., 2004; Ma et al., 2006). It was discovered
based upon its ability to mediate upregulation of the glycolytic
enzyme liver pyruvate kinase (Pklr) independent of insulin
signaling in primary hepatocytes exposed to high-glucose cul-
ture media (Yamashita et al., 2001). However, in vivo, fructose,
but not glucose, gavage acutely and robustly upregulates the
expression of hepatic ChREBP-beta, a potent ChREBP isoform,
along with its fructolytic, glycolytic, and lipogenic targets (Kim
et al., 2016). Liver-specific ChREBP knockdown or knockout
prevents sucrose- and fructose-mediated induction of DNL en-
zymes and DNL activity (Erion et al., 2013; Kim et al., 2017;
Linden et al., 2018).
In humans, genetic variants in the ChREBP locus are strongly
associated with increased circulating triglyceride levels and
reduced HDL-cholesterol levels, the dyslipidemia characteristi-
cally associated with the metabolic syndrome (Kooner et al.,
2008). Fructose consumption acutely increases ChREBP activ-
ity, which has been observed in livers of humans with obesity,
diabetes, and fatty liver disease (Eissing et al., 2013; Kursawe
et al., 2013). This suggests that ChREBP links hepatocellular
hexose availability to both DNL, as well as very-low-density lipo-
protein (VLDL) packaging and export and may mediate the DNL
and hypertriglyceridemia after fructose feeding in individuals
with obesity and insulin resistance. Recent evidence demon-
strates that genetic variants in the ChREBP locus interact with
sugar consumption to impact circulating lipids in human popula-
tions, further supporting a role for ChREBP as a central mediator
of sugar’s effects on cardiometabolic lipid risk factors in people
(Haslam et al., 2021). ChREBP may serve a similar function to
promote DNL and chylomicron packaging in enterocytes after
fructose feeding (Haidari et al., 2002).
Liver ChREBP knockdown in fructose-fed rats reduced circu-
lating triglyceride levels, confirming a role for ChREBP in fruc-
tose-mediated dyslipidemia (Erion et al., 2013). The effects of
ChREBP on circulating triglycerides are likely mediated through
its regulation of key enzymes involved in VLDL packaging and
export, including microsomal triglyceride transfer protein (Mttp)
and transmembrane 6 superfamily, member 2 (Tm6sf2) (Lei
et al., 2020; Niwa et al., 2018). Hepatic ChREBP may also limit
circulating triglyceride clearance through its ability to stimulate
production of proteins, such as apolipoprotein C3 (Apoc3) and

Review
angiopoietin-like 8 (Angptl8), which inhibit lipoprotein lipase (Lpl)
activity and the clearance of circulating triglycerides (Caron
et al., 2011; Fu et al., 2014). Although liver-specific ChREBP
knockout or knockdown fully abrogates DNL, under some condi-
tions, this has little or no effect on steatosis (Erion et al., 2013;
Kim et al., 2017; Linden et al., 2018). Linden et al. suggested
that the reduction in DNL in ChREBP KO mice is balanced by a
reduction in VLDL packaging export, leading to little net change
in liver fat content (Linden et al., 2018). Additionally, although
DNL is a significant contributor to steatosis, particularly in pa-
tients with obesity and NAFLD, the majority of lipid in steatotic
livers originates from circulating free fatty acids rather than
DNL (Donnelly et al., 2005; Smith et al., 2020). These results high-
light that DNL and steatosis are regulated by distinct processes
and can be dissociated from each other. The importance of DNL
to both NAFLD and the dyslipidemia of metabolic syndrome re-
quires further investigation.
ChREBP does not act alone in regulating the expression of
DNL enzymes and other mediators of lipid homeostasis. The ste-
rol regulatory element-binding protein 1c (SREBP1c) is another
master regulator of lipogenic enzymes that responds to both nu-
trients and hormones (Shimano and Sato, 2017). The effects of
ChREBP and SREBP1c are synergistic on lipogenic targets
(Linden et al., 2018). Insulin strongly promotes SREBP1c activity
via a pathway that is dependent on AKT and mechanistic target
of rapamycin complex 1 (mTORC1) (Shimano and Sato, 2017).
Although fructose does not directly stimulate insulin secretion,
increased adiposity and hyperinsulinemia associated with
chronic consumption of fructose might enhance SREBP1c ac-
tivity.
Along with activation of ChREBP, fructose feeding can activate
SREBP1c independently of hepatic insulin signaling in liver-spe-
cific insulin receptor-knockout mice (Haas et al., 2012). Recent
work indicates that DHAP, a product of both glycolysis and fruc-
tolysis, provides a signal to activate mTORC1, which is important
in activating SREBP1c (Orozco et al., 2020). However, fructose
feeding appears to inhibit, rather than activate, mTOR (Hu
et al., 2018). The mechanisms mediating fructose-induced acti-
vation of SREBP1c remain uncertain. Additional recent evidence
in humans supports the hypothesis that increased lipogenic
enzyme expression and lipogenesis in NAFLD patients is depen-
dent on substrate-derived signals, rather than systemic hormonal
cues, activating both ChREBP and SREPB1c (Ter Horst
et al., 2020).
Some, but not all, studies suggest that fructose consumption
promotes ER stress, which may also induce proteolytic cleavage
and activation of SREPB1c (Flamment et al., 2012; Kammoun
et al., 2009; Kim et al., 2017; Marek et al., 2015). ER stress can
also activate the transcription factor XBP1, which may enhance
the expression of lipogenic enzymes independently of other lipo-
genic transcription factors (Lee et al., 2008; Marek et al., 2015).
PPAR-g coactivator 1b (PGC-1b) is a transcriptional coactiva-
tor that can enhance transcriptional activity of both ChREBP and
SPREBP1c, as well as other important metabolic transcription
factors, including PPAR-g, PPAR-a, estrogen-related receptors
(ERRs), and liver X receptor (LXR) (Chambers et al., 2013; Lin
et al., 2002, 2005a, 2005b). In fructose-fed rats, the knockdown
of hepatic PGC-1b prevented increases in adiposity, lipogen-
esis, steatosis, hyperinsulinemia, and hypertriglyceridemia (Na-
ll
gai et al., 2009). As a result, PGC-1b appears to promote multiple
adverse sugar-mediated phenotypes and poses interesting po-
tential as a therapeutic target.
Recent work has recast the role of fructose as a lipogenic sub-
strate within hepatocytes. The path by which fructose-derived
intermediates can be used as substrates for fatty acid synthesis
within hepatocytes requires synthesis of citrate in the mitochon-
dria, which is then exported from the mitochondria and cleaved
by ATP citrate lyase (Acly) to generate cytosolic acetyl-CoA, the
primary precursor for new fat synthesis (Sul et al., 1984). Con-
trary to conventional wisdom, Zhao and colleagues showed
that fructose-derived carbons could be incorporated into the
newly synthesized fatty acids in the liver in Acly knockout
mice, demonstrating that fructose-derived citrate is not required
for its use in DNL (Zhao et al., 2020). In this study, fructose car-
bons were used as lipogenic substrate via an indirect path. Fruc-
tose catabolized by microbiota in the distal gut to acetate was
absorbed, transported via the portal vein, taken up by hepato-
cytes, and converted to acetyl-CoA by an acetyl-CoA synthetase
(Acss2). When fructose was consumed more gradually, both the
conventional, direct citrate pathway and the microbiota-acetate
pathway appeared to contribute fructose carbons to the newly
synthesized fatty acids (Zhao et al., 2020).
Fructose-derived metabolites may provide signals that regu-
late additional aspects of intermediary metabolism. For instance,
the second step in DNL is mediated by acetyl-CoA carboxylase
(ACACA), which catalyzes the carboxylation of acetyl-CoA, the
rate-limiting step in DNL, to generate malonyl-CoA (López-Casil-
las et al., 1988). Malonyl-CoA serves as an important signaling
molecule, as it potently inhibits carnitine palmitoyltransferase
1A (Cpt1a), an enzyme required for translocation of fatty acids
into the mitochondria (McGarry, 2002). Thus, fructose-derived
signals also serve to inhibit fatty acid oxidation (Topping and
Mayes, 1972). Recent evidence suggests that fructose-derived
metabolites might also be used to post-translationally modify
mitochondrial proteins, including Cpt1a, which may also
contribute to the inhibition of fatty acids (Softic et al., 2019). In-
hibiting fatty acid oxidation is another mechanism by which fruc-
tose-derived signals may contribute to the development of
steatosis.
FRUCTOSE AND NAFLD
Hepatic steatosis constitutes the earliest stage of NAFLD and is
diagnosed when more than 5% of liver cells contain lipid droplets
on biopsy or, more commonly, by specific estimates of liver fat
content based on imaging. In 10%–15% of individuals, steatosis
progresses to non-alcoholic steatophepatitis (NASH), which is
characterized by inflammation and fibrosis and, in turn, may
evolve further to cirrhosis and increased risk for hepatocellular
carcinoma. In individuals with NAFLD, steatosis strongly associ-
ates with increased DNL and variably associates with changes in
VLDL secretion and fat oxidation (reviewed in Ter Horst and Ser-
lie, 2017). Because of fructose’s ability to promote DNL and
inhibit fat oxidation, investigators have posited that fructose con-
sumption is a major driver of NAFLD (Jensen et al., 2018; Lim
et al., 2010). Although studies administering very high doses of
fructose support the possibility that fructose promotes steatosis
in humans, so far, evidence that fructose when consumed at
Cell Metabolism 33, December 7, 2021 2341
 ll
levels typical of Western diets is associated with the develop-
ment of NAFLD is mixed. This pertains to both prospective
epidemiological cohorts evaluating sugar and fructose con-
sumption, as well as short-term intervention studies comparing
the addition of isocaloric fructose versus glucose (Agebratt
et al., 2016; Chiu et al., 2014; Chung et al., 2014; Kanerva
et al., 2014; Ma et al., 2015; Ouyang et al., 2008; Schwarz
et al., 2015). Two fructose restriction studies support the possi-
bility that reducing fructose consumption, even isocalorically, re-
duces DNL and liver fat in humans, but these studies lacked con-
trol arms, which limit definitive conclusions (Schwarz et al., 2017;
Volynets et al., 2013). Recently, a small, well-controlled sugar re-
striction study was performed in adolescent boys with histolog-
ical evidence of NAFLD (Schwimmer et al., 2019). Free sugars
were restricted to less than 3% of daily calories for 8 weeks
and this was compared with ‘‘regular’’ diet controls. Sugar re-
striction was associated with a greater reduction in liver fat, as
well as a greater reduction in alanine aminotransferase, a circu-
lating marker of liver injury. In the last year, another small, well-
controlled restriction study was completed in overweight adults
(Simons et al., 2021). Dietary fructose was restricted to less than
10 g per day, and individuals were randomly assigned to supple-
mentation with fructose to achieve fructose intake similar to
baseline (control group) or isocaloric glucose over 6 weeks (re-
striction group). The fructose-restricted group achieved small,
but statistically significant, reductions in liver fat compared
with controls (Simons et al., 2021). Perhaps the most compelling
evidence that fructose is a common contributor to NAFLD de-
rives from a clinical study in which participants with steatosis
were administrated a KHK inhibitor, thus blocking fructose meta-
bolism in the liver, intestines, and kidneys (Kazierad et al., 2021).
Participants with a mean baseline liver fat of 15% were asked to
maintain their normal diets without fructose supplementation for
6 weeks, during which time they were treated with either one of
two doses of KHK inhibitor or placebo. At the end of the study,
study participants who took the higher dose of KHK inhibitor
demonstrated a greater than 18% reduction in liver fat compared
with placebo. These data strongly support the proposal that
quantities of fructose typical of a modern Western diet contribute
significantly to the increasing prevalence of NAFLD.
A minority of patients with NAFLD progress to more advanced
forms of liver injury involving inflammation and fibrosis. Some ev-
idence suggests that increased fructose consumption may pro-
mote progression to more advanced forms of NAFLD in children,
adolescents, and adults (Abdelmalek et al., 2010; Mosca et al.,
2017). The ability of fructose to promote progression could be
due to its effects on enhancing lipogenesis and steatosis, but
other mechanisms related to unique aspects of its metabolism
could also contribute. Emerging data suggest that hepatocellular
energy homeostasis is abnormal in NAFLD, and these energetic
derangements may be exacerbated by fructose. As previously
noted, the rapid increase in hexose phosphates and the depletion
of ATP that can result from fructose phosphorylation within hepa-
tocytes can be detected non-invasively by 31P magnetic reso-
nance spectroscopy (MRS). Using this and related techniques,
the majority of MRS studies detect alterations in energy status
in the livers of patients with NAFLD (Abrigo et al., 2014; Bawden
et al., 2016; Cortez-Pinto et al., 1999; Karczmar et al., 1989; Nair
et al., 2003; Traussnigg et al., 2017). A pilot study suggested that
2342 Cell Metabolism 33, December 7, 2021
Review
after administration of fructose, recovery of energy status is de-
layed in the livers of patients with NASH (Cortez-Pinto et al.,
1999). However, follow-up studies in participants with obesity
showed mixed results (Bawden et al., 2016; Nair et al., 2003).
These human studies are complemented by studies performed
in fructose-fed mice (Lanaspa et al., 2012; Softic et al., 2019).
Fructose feeding produced evidence of altered mitochondrial
morphology, an altered mitochondrial proteome, and increased
reactive oxygen species that could potentially adversely impact
mitochondrial function and contribute to changes in energy sta-
tus and liver disease (Lanaspa et al., 2012; Softic et al., 2019).
Recent investigations have focused not only on the direct ef-
fects of fructose metabolism within the liver but also indirect ef-
fects potentially mediated by changes in the microbiome and gut
barrier function. Complex associations between changes in the
gut microbiome and NAFLD are of increasing interest (Sharpton
et al., 2021). Unabsorbed fructose serves as fuel for the intestinal
microbiota and may contribute to a wide range of changes in in-
testinal microbial communities (reviewed in Lambertz et al.,
2017). Fructose-dependent alterations in the intestinal micro-
biota or direct effects on the epithelial cells may disrupt barrier
function, leading to the progression of NAFLD due to increased
intestinal permeability (Bergheim et al., 2008). This may increase
TNF-alpha and endotoxin in the portal blood, effects that can be
attenuated with antibiotics (Bergheim et al., 2008; Todoric et al.,
2020). Recent work suggests that prolonged exposure to 30%
fructose in drinking water causes ER stress within colonic enter-
ocytes, leading to barrier breakdown and endotoxemia in mice
(Todoric et al., 2020). This endotoxemia induces TNF-alpha in
liver myeloid cells, which can induce ER stress in hepatocytes,
leading to cleavage and activation of SREBP1 (Kim et al.,
2018; Todoric et al., 2020). However, in normal physiological cir-
cumstances, little ingested fructose reaches the colon. Indeed,
2 weeks of fructose supplementation in a small preliminary pro-
spective cohort of adults with obesity did not show any changes
in microbiome, fecal metabolites, or indices of gut permeability,
inflammation, or endotoxemia (Aleman et al., 2020).
FRUCTOSE EFFECTS ON GLUCOSE HOMEOSTASIS
Along with changes in liver fat and circulating triglycerides, short-
term hypercaloric sucrose or fructose feeding can rapidly induce
fasting hyperinsulinemia in humans and animal models (Lê et al.,
2009; Reaven, 1988; Ter Horst et al., 2016). This occurs despite
the fact that fructose in isolation does not stimulate insulin secre-
tion from pancreatic beta cells (Curry, 1989). Presumably, this
hyperinsulinemia is an indicator of liver and/or peripheral insulin
resistance. In rats, the dose and duration of sugar exposure have
significant effects on which tissues are affected. Compared with
glucose, very high doses of fructose and sucrose (>60% of total
energy) can induce both hepatic and peripheral insulin resis-
tance within 2 months. However, more moderate doses (
18%
of total energy) for twice as long elicited isolated hepatic insulin
resistance (Pagliassotti and Prach, 1995; Pagliassotti et al.,
1994; Thresher et al., 2000). Similar to the case in rodents, isoca-
loric and moderate hypercaloric fructose feeding in humans has
preferential effects to induce hepatic over peripheral insulin
resistance (Aeberli et al., 2013; Schwarz et al., 2015; Ter Horst
et al., 2016).

Review
Pagliassotti and colleagues noted that gluconeogenic capac-
ity was increased in primary hepatocytes isolated from high
sucrose and fructose feeding, possibly due to a fructose-depen-
dent increase of glucose-6-phosphatase (G6pc), the final enzy-
matic step of glucose production (Bizeau et al., 2001; Wei
et al., 2004). ChREBP is essential for fructose-mediated upregu-
lation of both intestinal and hepatic G6pc (Kim et al., 2016; Ped-
ersen et al., 2007). The ChREBP-mediated increase of G6pc is
dominant over the antagonistic action of insulin to suppress it
(Kim et al., 2016). This ChREBP-G6pc signaling axis is
conserved in humans and likely contributes to hepatic insulin
resistance in humans in the setting of high-sugar diets (Kim
et al., 2016). Hepatic ChREBP knockdown in rats also attenuated
peripheral insulin resistance by an unknown mechanism (Erion
et al., 2013). Recent work demonstrated that knocking out
KHK in mice prevented fructose-induced changes in adipose
inflammation, insulin resistance, and a decline in circulating adi-
ponectin (Marek et al., 2015). Mechanisms linking fructose meta-
bolism to changes in adipose function are uncertain. Fructose
may also cause hepatic insulin resistance by impairing hepatic
insulin signaling (Softic et al., 2020). Fructose-induced ER stress
and associated JNK kinase activation and signaling have been
invoked as a cause of hepatic insulin resistance (Sun et al.,
2015; Wei and Pagliassotti, 2004; Wei et al., 2005). As fructose
feeding may cause steatosis and steatosis is commonly associ-
ated with hepatic insulin resistance, one or more of the many
putative lipid mediators implicated in lipid-mediated insulin
resistance may be involved (Petersen and Shulman, 2018). For
instance, fructose feeding has been associated with diacylgly-
cerol accumulation, PKC activation, and impaired insulin-medi-
ated AKT2 activation (Jurczak et al., 2012; Nagai et al., 2009).
One other distinct mode of fructose-mediated hepatic insulin
resistance has been described. Coate and colleagues noted
that hepatic glucose uptake was impaired in both high-fat and
high-fructose fed dogs (Coate et al., 2010, 2014). Whereas fat
impaired hepatic insulin action and AKT phosphorylation, fruc-
tose did not. Rather, fructose impaired hepatic Gck protein
expression, Gck activity, and hepatic glycogen synthesis. The
mechanism mediating fructose’s negative effects on hepatic
Gck is unknown.
Recent work indicates that fructose metabolism in the liver
may also regulate systemic amino acid metabolism. In particular,
fructose-mediated activation of ChREBP upregulates and down-
regulates BCKDK and PPM1K, respectively (White et al., 2018).
BCKDK is a kinase that phosphorylates and inhibits BCKDH, the
rate-limiting step in branched-chain amino acid (BCAA) oxida-
tion (White and Newgard, 2019). This phosphorylation and inhibi-
tion are reversed by the phosphatase PPM1K. As the liver is a
major site of BCAA oxidation, this mechanism may contribute
to the long-standing observation that increased circulating
branched-chain amino acids are associated with insulin resis-
tance and impaired glucose homeostasis in humans (Newgard
et al., 2009; White and Newgard, 2019).
EFFECTS OF FRUCTOSE ON APPETITE,
MACRONUTRIENT PREFERENCE, AND OBESITY
The hedonic reward derived from consuming sugars containing
fructose contributes to its overconsumption, leading to exces-
ll
sive energy intake, overweight, and obesity. Additional mecha-
nisms independent of its hedonic value have also been invoked
to explain why fructose might be particularly obesogenic. For
instance, fructose ingestion may have distinct effects on anorex-
igenic and orexigenic hormones, such as leptin and ghrelin, that
impact feeding behaviors. Meal-associated increases in leptin
are diminished by fructose compared with glucose and fructose
may induce leptin resistance (Chotiwat et al., 2007; Shapiro
et al., 2008; Teff et al., 2004). Fructose ingestion less potently
suppresses ghrelin secretion compared with glucose ingestion
(Teff et al., 2004). All these effects could promote excessive
food intake and weight gain.
Recent evidence derived from human genetics and non-clin-
ical model organisms has suggested a negative feedback loop,
whereby the consumption of fructose suppresses further sugar
consumption. FGF21 is a liver-derived hormone that regulates
systemic fuel homeostasis (Flippo and Potthoff, 2021). In hu-
mans, non-human primates, and rodents, fructose consumption
acutely and robustly increases hepatic production of FGF21 in a
ChREBP-dependent manner (Dushay et al., 2015; Iizuka et al.,
2009; Kim et al., 2017; Talukdar et al., 2016). FGF21 signals via
neural circuitry, including through glutamatergic neurons in the
ventromedial hypothalamus, to suppress further carbohydrate
intake (von Holstein-Rathlou et al., 2016; Jensen-Cody et al.,
2020; Talukdar et al., 2016). Moreover, common genetic variants
in the FGF21 locus associate with sugar versus fat preferences in
human populations (Chu et al., 2013; Tanaka et al., 2013).
The effect of fructose to suppress further carbohydrate con-
sumption may confound interventional trials that aim to study
the metabolic effects of added sugars. Indeed, multiple rigorous
studies have found that supplemental sugar markedly reduced
spontaneous consumption of other carbohydrates, limiting dif-
ferences in total sugar consumption between experimental and
control participants (Ebbeling et al., 2020; Maersk et al., 2012).
This strong, negative feedback loop must be considered when
designing and interpreting dietary intervention trials.
FRUCTOSE CONTRIBUTIONS TO DYSREGULATED
BLOOD PRESSURE
Whereas extreme fructose-enriched diets can induce hyperten-
sion in rodents, the association between SSB consumption and
hypertension in humans is weaker, particularly when compared
with other cardiometabolic risk factors (Hwang et al., 1987;
Khan and Sievenpiper, 2016). Potential mechanisms by which
fructose may affect blood pressure include effects on intestinal
salt absorption, renal salt absorption and function, or endothelial
function (reviewed in Klein and Kiat, 2015). Further, based on
epidemiological associations and interventional studies in ani-
mal models, Johnson and colleagues have proposed that
fructose-induced hyperuricemia is a major contributor to the
deleterious metabolic effects of fructose, including its adverse
effects on kidney function, blood pressure, and cardiovascular
risk (Ejaz et al., 2020). However, most but not all Mendelian
randomization studies indicate that genetic variants that causally
affect uric acid levels and the risk of gout do not associate with
other adverse cardiometabolic traits (Ge et al., 2020; Jordan
et al., 2019; Tin et al., 2019; Yang et al., 2010). Moreover, recent
randomized, prospective interventional trials in humans aimed at
Cell Metabolism 33, December 7, 2021 2343
 ll
reducing uric acid production did not show benefits in patients
with type 1 diabetes or chronic kidney disease (Badve et al.,
2020; Doria et al., 2020). Thus, although uric acid production re-
mains an excellent marker of fructose metabolism, its causal role
in fructose-associated pathologies remains controversial.
Fructose feeding may promote hypertension by enhancing in-
testinal salt absorption (Barone et al., 2009; Singh et al., 2008).
Fructose induces the intestinal anion exchanger Slc26a6 in a
GLUT5-dependent manner, and Slc26a6 knockout mice are
resistant to fructose-induced hypertension, but not to other
adverse metabolic effects of fructose feeding (Barone et al.,
2009; Singh et al., 2008). Fructose consumption suppressed
renin expression consistent with salt overload, and reduced
renal salt excretion, which may further contribute to fructose-
induced hypertension. The effects of fructose on increased
blood pressure may be synergistic with high-salt diets (Cabral
et al., 2014). Recent work suggests that fructose may also sensi-
tize the proximal tubule to angiotensin II and promote renal salt
reabsorption (Gonzalez-Vicente et al., 2018; Yang et al., 2020).
Additionally, KHK-mediated fructose metabolism within the
proximal tubule may enhance salt reabsorption by activating
the sodium hydrogen exchanger (Slc9a3) (Hayasaki et al.,
2019; Queiroz-Leite et al., 2012). As fructolytic enzymes are ex-
pressed at high levels in the renal proximal tubule, the role of
renal fructose metabolism as it relates to renal salt handling
will likely be of growing interest.
ENDOGENOUS PRODUCTION AS A MODIFIABLE
EXPOSURE?
Although nearly all public health attention and most scientific
research has focused on the metabolic effects of excessive die-
tary fructose, fructose is also synthesized endogenously from
glucose through the sorbitol (polyol) pathway. In this pathway,
glucose is reduced by aldose reductase (AR, also known as
Akr1b1 in humans and Akr1b3 in mice) to sorbitol, which is
then oxidized to fructose by sorbitol dehydrogenase (SORD).
Endogenously produced fructose appears to play a role in
fertility, as it is a major energy source for sperm (Frenette et al.,
2006; Jayaraman et al., 2014; Martini et al., 2010). Sorbitol, the
immediate precursor for fructose production, is also produced
by the placenta (Hwang et al., 2015). In fasted adult humans,
circulating plasma fructose is detectable in the low micromolar
range, consistent with some degree of endogenous production,
and it tends to be higher in men than in women, and is possibly
related to production in the testes (Chen et al., 2020).
Recently, Francey et al. measured endogenous fructose pro-
duction rates of
5.6–16.7 g/day in vivo in healthy human partic-
ipants (Francey et al., 2019). Fructose production acutely
increased with sugar consumption (Francey et al., 2019). An
endogenous fructose production rate of 17 g/day is approxi-
mately one-third of the average daily consumption of fructose
in the US population and thus a substantial fraction of total fruc-
tose exposure in many people (Marriott et al., 2009). Indeed, this
is roughly equivalent to the fructose in a can of regular soda—an
amount that when consumed daily is associated with increased
cardiometabolic risk (Green et al., 2014).
Increased fasting fructosemia is associated with higher fasting
glucose and the risk of incident T2D (Chen et al., 2020). Because
2344 Cell Metabolism 33, December 7, 2021
Review
fructose is produced endogenously from glucose, this may sug-
gest that increased endogenous fructose production is a marker
of worsening glycemia. However, even after adjustment for
baseline glucose levels and SSB consumption, fasting blood
fructose levels is associated with an increased risk of incident
T2D in a dose-dependent manner, possibly due to a pathogenic
‘‘feedforward’’ loop whereby increased blood glucose stimu-
lates fructose production, which, in turn, exacerbates T2D and
cardiometabolic risk (Chen et al., 2020).
The increased serum, urine, and tissue sorbitol concentrations
present in individuals with diabetes have been implicated in the
development of diabetic microvascular complications (Brownlee,
2005; Lorenzi, 2007; Oates, 2002; Preston and Calle, 2010). The
activity of polyol pathway may vary significantly within the popu-
lation (Yoshii et al., 2001), raising the possibility that people with
increased sorbitol and fructose production may be at higher risk
of developing T2D and its complications. Although sorbitol levels
decrease in response to improved glycemic control in T2D, some
studies suggest that elevated sorbitol and fructose levels are
more refractory to normalization of glycemia in some groups of
patients, again indicating that increased endogenous fructose
production may contribute to the pathogenesis of T2D (Yoshii
et al., 2001). Further studies are needed to better understand
the causal relationship between circulating glucose concentra-
tions and endogenous fructose production. However, current
knowledge is compatible with a model whereby increased flux
through the polyol pathway, leading to increased endogenous
fructose production, may present a significant, unappreciated
risk factor of developing T2D and its complications.
Studies in animal models also provide evidence of substantial
endogenous fructose production. Indeed, micromolar circu-
lating fructose can be measured in GLUT5 knockout mice on
fructose-free diets (Patel et al., 2015c). Moreover, the inhibition
of fructose metabolism by global deletion of KHK in mice leads
to a 30-fold increase in circulating fructose on fructose-free diets
(Patel et al., 2015c). Findings in animal models also support a
pathologic role for endogenous fructose production in metabolic
disease (Lanaspa et al., 2013, 2014; Oppelt et al., 2015). Mice
exposed to 10% glucose in drinking water develop features of
metabolic syndrome, including increased visceral adiposity, hy-
perinsulinemia, and fatty liver (Lanaspa et al., 2013). This effect is
blunted in both AR-deficient and KHK-deficient mice (Lanaspa
et al., 2013). As previously noted, mice with mutations in Aldob,
the enzyme required for catabolism of F1P, develop significant
steatosis even on diets free of fructose, indicating that endoge-
nously produced fructose is sufficient to contribute to metabolic
dysfunction in this model (Oppelt et al., 2015).
Sorbitol is a major intracellular osmolyte in the renal medulla,
where its production can be increased by hypertonicity through
the induction of AR expression (Bagnasco et al., 1987). Theoret-
ically, high-salt diets might enhance endogenous fructose
production within the kidney through this mechanism. Unexpect-
edly, Lanaspa and colleagues have observed that gavaging mice
with hypertonic fluids induced AR expression in the liver and hy-
pothalamus and have proposed that endogenous fructose
production is a conserved cellular program in response to hyper-
tonicity in multiple tissues and that high-salt diets may contribute
to metabolic disease through this mechanism (Lanaspa et al.,
2018b). Additional potential links between fructose metabolism,

Review
the regulation of volume and hydration status, and metabolic dis-
ease include the observation that fructose feeding can induce
vasopressin secretion and that vasopressin activity through the
vasopressin V1B receptor (Avpr1b) may contribute to the adverse
metabolic effects of fructose (Andres-Hernando et al., 2021).
CONCLUSIONS
The last 5 years have witnessed major advancements in our un-
derstanding of the molecular physiology of fructose metabolism
and its potential contribution to metabolic disease. One conclu-
sion, firmly established in recent years, is that excessive fructose
metabolism within the liver is a major source of fructose-associ-
ated morbidity. Over the next 5 years, we anticipate further prog-
ress in defining key molecular mechanisms by which hepatic
fructose metabolism participates in disease pathogenesis. We
are hopeful that mechanisms defined through these studies will
be useful not only to understand fructose-associated disease
but may also generalize to other forms of metabolic disease asso-
ciated with obesity and overnutrition. Recent work has also es-
tablished that intestinal fructose metabolism may be protective.
Defining mechanisms and pathways to enhance intestinal fruc-
tose metabolism seems a promising alternative or complemen-
tary therapeutic approach. Whereas fructose metabolism within
the intestine may be protective, the role of other fructose meta-
bolism in other tissues, such as the kidney, remains to be firmly
established. With the availability of conditional genetic mouse
models, we expect that this and related questions will be ad-
dressed in short order.
Advances in targeting fructose metabolism pharmacologically
for therapeutic purposes have paralleled the advancements in
our understanding of its molecular physiology. Initial results in
early-stage clinical trials appear promising. Larger and longer-
term studies will be required to determine efficacy and safety
in diverse clinical settings with potential applications in popula-
tions with NAFLD and diabetes.
The pharmacological and physiological data continue to sup-
port recommendations to limit sugar consumption. Along with
the advancements in molecular physiology and pharmacology,
establishing the efficacy of public health efforts to reduce sugar
consumption will remain an important goal for the foreseeable
future.
ACKNOWLEDGMENTS
This work was supported by NIH grants R01DK100425 and 5R01DK121710
and the American Heart Association (16CSA28590003) (M.A.H.). Illustrations
created with BioRender.com.
DECLARATION OF INTERESTS
M.A.H. received research support from Eli Lilly and Co. M.J.B. is an employee
and shareholder of Pfizer, which holds patent US20170183328A1.
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