The Liver as an Endocrine Organ—Linking NAFLD

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The Liver as an Endocrine Organ—Linking NAFLD
and Insulin Resistance
Matthew J. Watt,1 Paula M. Miotto,1 William De Nardo,1 and Magdalene K. Montgomery1
1
Department of Physiology, University of Melbourne, Melbourne, Victoria 3010, Australia
ORCiD numbers: 0000-0003-4064-4188 (M. J. Watt).
ABSTRACT The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic
glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most
common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of
advanced mass spectrometry “omics” approaches and detailed experimentation in cells, mice, and humans, we now understand that
the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert
powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving
field of “hepatokine” biology with a particular focus on delineating previously unappreciated communication between the liver and
other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs,
and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize
the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for
intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD. (Endocrine Reviews 40:
1367 – 1393, 2019)
N onalcoholic fatty liver disease (NAFLD) is

defined by the accumulation of fat in the
liver, in the absence of excessive alcohol con-
threatening conditions such as cirrhosis, hepato-
cellular carcinoma, and terminal liver failure. Ap-
proximately % of adults in industrialized countries
sumption and other causes of hepatic steatosis, and have NAFLD, and the global epidemic of obesity is
encompasses a spectrum of conditions. Hepatic driving a dramatic increase of NAFLD that is fore-
steatosis is also known as nonalcoholic fatty liver casted to result in increased clinical and economic
(NAFL) and is clinically characterized by the burden (, ).
presence of visible lipid droplets containing tri- Hepatic steatosis/NAFL or early stage NAFLD
glycerides in .% of hepatocytes when thin sec- is often described as a “benign condition” in the
tions are assessed by light microscopy (, ), or a context of liver disease; however, the effects of
threshold of ..% when using proton magnetic steatosis extend beyond the liver. There are strong
resonance spectroscopy (). Liver lipid levels are epidemiological links between NAFLD and type 
regulated by the interplay between the delivery of diabetes, and steatosis is strongly associated with
lipids to the liver and their hepatic uptake, syn- insulin resistance in the liver, and also in pe-
thesis, oxidation, and secretion within very low– ripheral tissues such as skeletal muscle and adi-
density lipoproteins (VLDLs). Alterations in the pose tissue (–). A major focus of current ISSN Print: 0163-769X
equilibrium of one or more of these processes can research is understanding the pathogenic mech- ISSN Online: 1945-7189
promote hepatic steatosis (). NAFL can further anisms linking these comorbidities, and in this Printed: in USA
Copyright © 2019
progress to nonalcoholic steatohepatitis (NASH), review, we focus on the impact of NAFLD on
Endocrine Society
which is defined by hepatocyte ballooning, necrosis altering the endocrine function of the liver, and Received: 24 January 2019
near steatotic hepatocytes, and mild inflammation, how the secretion of proteins, metabolites, and Accepted: 4 April 2019
with or without different stages of fibrosis (). nucleic acids contributes to the pathophysiology First Published Online:
Further progression of NASH can lead to life- of insulin resistance. 25 April 2019
doi: 10.1210/er.2019-00034 https://academic.oup.com/edrv 1367

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ESSENTIAL POINTS
· Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes and is the most
common chronic liver disorder worldwide, affecting ~25% to 30% of adults in industrialized countries
· NAFLD is strongly associated with metabolic comorbidities, including obesity, type 2 diabetes, and dyslipidemia
· The liver secretes proteins, metabolites, and noncoding RNA that act as autocrine/paracrine and endocrine factors to
influence metabolism in other tissues
· “Hepatokines” exert pleiotropic effects on lipid and glucose metabolism, as well as insulin action, and their secretion is
impacted by NAFLD
· Liver-derived lipids and metabolites can serve as signaling molecules to regulate insulin action and other metabolic
processes
· Liver-derived miRNAs may regulate glycemic control in NAFLD; however, definitive evidence is lacking
NAFLD and Diabetes widely held idea that hepatic steatosis is a benign
condition, it is now clear that steatosis is closely linked
Prevalence to impaired insulin action and type  diabetes, and it is
Concurrent with the increased global prevalence of an early predictor of metabolic disorders, particularly
obesity (, ), NAFLD has emerged as the most in the normal-weight population (, ). Moreover,
common chronic liver disorder worldwide, affecting hepatic steatosis precedes the development of skeletal
~% to % of adults in industrialized countries, with muscle lipid accumulation, macrophage-related in-
~% of these NAFLD cases classified as NASH (, ). flammation, hepatic, skeletal muscle, and adipose tissue
Importantly, NAFLD prevalence is forecasted to in- insulin resistance, and whole-body hyperglycemia and
crease by % in the next  years, from . to . hyperinsulinemia (–) in mice fed a high-fat diet.
million individuals worldwide, with coincident in- Taken together, these observations are consistent with
creases in NASH and liver-related deaths (). Liver- the notion that changes occurring in the fatty liver alter
related deaths are likely due to the development of paracrine and endocrine functions to cause insulin
fibrosis (), which occurs in ~% of NAFLD patients resistance in key glucoregulatory tissues.
() and is a major clinical concern. Although hepatic steatosis is closely associated with
systemic insulin resistance, it is noteworthy that in-
NAFLD and insulin resistance
sulin resistance also predicts the development of
NAFLD is strongly associated with metabolic
NAFLD. This results primarily from an impaired
comorbidities, including obesity, type  diabetes, and
ability of insulin to suppress adipose tissue lipolysis,
dyslipidemia. Steatosis prevalence is increased in co-
leading to increased delivery of free fatty acids to the
horts with obesity undergoing bariatric surgery, ranging
liver (, ), and from increased de novo lipogenesis
from % to % (–), with NASH identified in %
to % (–). Type  diabetes mellitus is closely () that results from stimulation of lipogenic enzymes
associated with NAFLD, with more than three-fourths via sterol receptor–binding protein c (SREBP-c),
of type  diabetes patients reportedly having NAFLD even in an insulin-resistant state (). There is also
(–). evidence that triglyceride synthesis is increased through
Hepatic steatosis is epidemiologically associated the Kennedy pathway () and that b-oxidation of
with insulin resistance (, –). Results from small fatty acids is decreased in insulin resistance, although
cross-sectional studies using gold-standard measures of the latter is controversial (–).
insulin action have consistently shown that hepatic Although the association between NAFLD and
steatosis, independent of adiposity, is associated with insulin resistance in generally clear in most patients,
impaired insulin action in liver, skeletal muscle, and this does not always hold true for specific geneti-
adipose tissue in both lean individuals and nondiabetic cally determined forms of fatty liver. For example,
individuals with obesity (–). Moreover, relatively a frequent sequence variation (IM) in patatin-
small increases in liver fat are associated with hepatic like phospholipase domain–containing protein 
and skeletal muscle insulin resistance, and further ac- (PNPLA) is strongly associated with fatty liver disease
cumulation of liver fat beyond this relatively low in the absence of insulin resistance or dyslipidemia
threshold (~.% for liver insulin resistance and ~% for (–), and similar dissociations are reported in
muscle insulin resistance) is not associated with more individuals with a single nucleotide polymorphism for
severe insulin resistance (). Thus, in contrast to the acyl-coenzyme A (CoA):diacylglycerol acyltransferase
1368 Watt et al Liver Hepatokines and Metabolic Disease Endocrine Reviews, October 2019, 40(5):1367–1393
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() and the Lys allele in transmembrane  su- secretory vesicles or secretory granules for delivery of
perfamily  (TMSF) (). In fact, the TMSF ac- transmembrane proteins to the plasma membrane and
tually protects from cardiovascular disease, despite soluble proteins to the extracellular space. Proteins
high liver fat content and high prevalence for pro- secreted in this manner contain a signal peptide on the
gression to NASH and cirrhosis (). These observa- N terminus and most often contain posttranslational
tions highlight the need to understand the mechanistic modifications that occur at the ER and Golgi (i.e.,
bases of NAFLD for predicting the development of glycosylation) ().
comorbidities and applicability of specific therapeutic
interventions. Nonclassical protein secretion
Proteins that do not contain an N terminus signal
peptide can be secreted as cargo contained within ex-
Liver Endocrine Function tracellular vesicles. There are three main types of ex-
tracellular vesicles that differ in terms of size, type of
Protein secretion—the role of “hepatokines” biogenesis, and composition. Exosomes are the smallest
The role of liver as a major secretory organ has long vesicle, ranging from ~ to  nm in diameter, and are
been appreciated, particularly with respect to its roles in formed within multivesicular bodies that fuse to the
regulating coagulation and hemostasis, but only recently plasma membrane and are released into the circulation
has the potential magnitude for protein secretion be- as exosomes. Microvesicles such as ectosomes and
come apparent. Mass spectrometry–based quantitative endosomes range from  to  nm and are formed
proteomics of human liver has quantified ~, by direct budding from the plasma membrane, whereas
proteins (), which parallels observations in mice (). apoptotic bodies range from  to  nm and are
Given that ~% of the transcripts in liver encode secreted as a byproduct of cell death (). These vesicles
secreted proteins (), there is clearly a large scope for contain protein, lipid, and nucleic acid cargo that
significant and varied protein secretion from the liver. somewhat reflects their cell of origin, and the compo-
The liver is composed of parenchymal cells, in- nents of extracellular vesicles can be rapidly altered in
cluding hepatocytes and bile duct cells, which occupy response to metabolic challenges (), highlighting their
~% of the liver volume, and nonparenchymal cells, potential role in regulating intertissue communication
such as sinusoidal endothelial cells, Kupffer cells, and and metabolism.
hepatic stellate cells. Although there are some differ-
ences in the proteins expressed in these different cell Hepatokines, NAFLD, and insulin resistance
types, the vast majority of liver proteins are expressed in Studies examining hepatocytes isolated from healthy
all liver cell types, and the hepatocyte proteome con- and steatotic mouse livers have used quantitative
stitutes the vast majority of the total liver proteome, proteomics to show that liver steatosis alters hep-
indicating that hepatocytes are quantitively the most atokine secretion and that the protein signals origi-
important cell type for liver protein secretion (). nating from the steatotic liver alter fatty acid
Several anatomical, structural, and functional fea- metabolism and induce inflammation and insulin
tures support the notion that the liver is an important resistance in other cell types. This section outlines the
organ for intertissue communication. The liver is large classically secreted hepatokines involved in regulating
(~. kg) and receives ~% of the cardiac output, lipid metabolism and insulin action, and it describes
providing a substantial volume of blood and thereby the effect of NAFLD in these relationships [see Table 
secreted factors for redistribution to other tissues. In this and Fig.  for hepatokine changes in the presence of
context, the liver has unique architecture and blood flow NAFLD (–)]. We close this section with a brief
regulation, whereby hepatocytes and nonparenchymal description of the literature pertaining to liver exo-
cells secrete products into the liver sinusoids, which flow some proteins and metabolism.
via the central veins to the inferior vena cava and
eventually to the heart for redistribution to peripheral Activin E
tissues. The extensive vascular network, and particularly Activin E is a member of the TGFb family and is
the “open pore” sinusoids that are located between encoded by the inhibin bE gene (). Activin E is a
hepatocyte planes, also supports the likelihood that newly identified hepatokine () that is elevated in
hepatokines are prominent in paracrine and autocrine liver and serum in humans with obesity () and
regulation of hepatocyte function. NAFLD (). Mice that overexpress activin E gain less
fat and have improved glucose tolerance when com-
Classical protein secretion pared with wild-type mice fed a high-fat diet. This
Classical or conventional secretion involves the appears to be mediated by an increase in uncoupled
transport of newly synthesized proteins through respiration as evidenced by increased expression of
the organelles of the secretory pathway, including thermogenic proteins in adipose tissue and higher core
the endoplasmic reticulum (ER), the ER exit sites, the temperature in activin E overexpressing mice (), as
Golgi, and eventually to the plasma membrane via well as an inability of activin E knockout mice to

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Table 1. Hepatokine Links With NAFLD and Insulin Resistance
Molecular
Gene (Mouse / Mass Expression Contribution to Glucose Tolerance/Insulin
Hepatokine Human) (kDa) in NAFLD Contribution to NAFLD Resistance
Activin E Inhbe/INHBE ~22a Increased Reduces steatosis (50) Activin E overexpression prevents diet-induced glucose
intolerance in rodents (51), unknown in humans
Adropin Enho/ENHO 5 Decreased Suppresses lipogenesis (52) Improves insulin sensitivity (52); stimulates insulin
signaling in skeletal muscle (53)
ANGPTL4 Angptl4/ANGPTL4 45 Increased Promotes hepatic lipid accumulation Controversial findings: (i) improves insulin sensitivity
(54–56) (55, 56) by decreasing hepatic glucose output (55);
(ii) causes insulin resistance in liver, skeletal muscle,
and adipose (57, 58)
DPP4 Dpp4/DPP4 ~30 Increased Increases liver CD36 (59), likely to Inhibits incretin levels and impairs insulin secretion
increase lipid storage (60)
Ectodysplasin EDA ~46 Increased Unknown Induces insulin resistance in skeletal muscle via JNK
activation (61)
Fetuin A Ashg/ASHG ~67 Increased Unknown Promotes insulin resistance in liver via ER stress and
JNK activation (62); inhibits insulin receptor in
skeletal muscle (63); ligand for TLR4, which
promotes lipid-mediated insulin resistance in
adipose tissue (64)
Fetuin B Fetub/FETUB ~60 Increased Unknown Promotes insulin resistance in myocytes/hepatocytes

(65); impairs whole-body glucose tolerance (65)
FGF21 Fgf21/FGF21 ~23 Increased Increases hepatic fat oxidation and decreases Improves insulin sensitivity, decreases diacylglycerol
lipids (66); decreases adipose tissue lipolysis, (68); promotes insulin secretion of pancreatic
reducing lipid availability to the liver (67) b-cells (69)
Follistatin Fst/FST 38 Increased Promotes IL-1b production, may promote Unknown

fibrosis development (70)
HFREP1 Fgl1/FGL1 36 Increased Promotes NAFLD (71); increases lipogenesis Causes insulin resistance in skeletal muscle via JNK
through ERK1/2 activation (72) activation (72)
HMGB1 Hmgb1/HMGB1 30 Increased Unresolved; blocking HMGB1 protects Unknown; however, HMGB1 activates TLR4 and
against NAFLD (73, 74) causes inflammation in hepatocytes that could
impair insulin sensitivity (75)
Inhibin bE Inbe 39 Increased Unknown Unknown

with
obesity
LECT2 Lect2/LECT2 16 Increased Unknown Promotes insulin resistance in skeletal muscle via JNK
activation (76); impairs insulin signaling via serine/
threonine phosphorylation of IRS1 (77)
PEDF Serpinf1/SERPINF1 50 Increased Interacts with ATGL to increase lipolysis; Promotes insulin resistance in skeletal muscle via JNK
ablation promotes steatosis (78, 79). activation (80).
RBP4 Rbp4/RBP4 21 Increased Unknown Equivocal. Overexpression in liver does not alter
glucose homeostasis or insulin sensitivity (81);
whole-body overexpression causes insulin resistance
by activating JNK and TLR4 (82)
SeP Selenop/SELENOP ~60 Increased Unknown Causes insulin resistance in skeletal muscle and liver
(83);inhibits the insulin receptor (83); impairs insulin
secretion from pancreatic b-cells (84)
SHBG Shbg/SHBG 95 Decreased Suppresses lipogenesis in liver, exacerbates Unknown

steatosis (85)
TSK Tsku/TSKU ~40 Increased Promotes steatosis and NASH (86) Associated with whole-body insulin resistance (86)
Abbreviation: ATGL, adipose triglyceride lipase.

aMolecular weight is predicted and requires form validation.
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maintain body temperature during cold exposure (). glucose tolerance, and lower fatty acid oxidation ().
Additionally, administration of recombinant activin E Although little is known regarding the direct effects of
to mice with activin E deficiency (via global knockout adropin on metabolism, acute IP injection of adropin
of follistatin-like ) resulted in hepatic steatosis, increases insulin signaling through protein kinase B
suggesting a role in regulating lipid metabolism (). (AKT) and AKT substrate of  kDa (AS)
The expression pattern in obesity is interesting, and phosphorylation, resulting in greater glucose trans-
potentially unexpected, as on the one hand plasma porter type  (GLUT) translocation to the sarco-
activin E levels are increased in individuals with lemma in skeletal muscle (). Consistent with these
obesity, but on the other hand mice with increased effects, acute administration of recombinant adropin
circulating activin E levels are resistant to weight gain. improves glucose homeostasis in insulin-resistant
Further studies are required to assess how activin E diet–induced obese mice, and it is associated with
drives uncoupled respiration and why this mechanism lower expression of lipogenesis-associated genes, in-
does not prevent weight gain in individuals with cluding sterol CoA desaturase  and fatty acid syn-
obesity. thase, in the liver and adipose tissue (). Others have
shown that adropin increases glucose uptake and
Adropin oxidation via activation of pyruvate dehydrogenase,
Adropin is encoded by the ENHO gene, and ex- the rate-limiting enzyme for mitochondrial pyruvate
pression is decreased in response to elevated hepatic transport, and is associated with downregulation of
lipid availability (). Serum adropin levels are lower in carnitine palmitoyl-transferase I (CPT) activity and
humans with obesity () and in patients with type  other proteins involved in lipid metabolism, including
diabetes (), and although there is no reported link the fatty acid transporter CD () (Table ). Hence,
between serum adropin and NAFLD in humans, high- high adropin expression and secretion appear to
fat feeding reduces ENHO expression in parallel with improve insulin sensitivity and carbohydrate and lipid
the development of hepatic steatosis in mice (). In metabolism while suppressing hepatic steatosis. Taken
line with these observations, hepatic steatosis is ex- together, these studies suggest that restoring adropin
acerbated in adropin-null mice, and this is accom- levels within the liver and/or blood of patients with
panied by impaired glucose tolerance and insulin obesity could be a therapeutic approach for NAFLD
sensitivity at the whole-body level () and, perhaps and insulin resistance.
paradoxically, increased hepatic and whole-body fatty
acid oxidation (). In agreement, hepatic steatosis Angiopoietin-like protein 4
resulting from high-fat feeding is attenuated in mice Angiopoietin-like protein  (ANGPTL) is secreted by
with adropin overexpression, and this occurs in par- liver and adipose tissue () and plays important roles
allel with enhanced whole-body insulin sensitivity, in regulating lipid metabolism. ANGPTL increases
Figure 1. General metabolic processes affected by hepatokines in NAFLD. Liver secretion of various proteins are altered with
NAFLD, and selected proteins can influence insulin responsiveness. In adipose and skeletal muscle, many hepatokines affect
pathways involved in inflammation, lipogenesis/lipolysis, and fatty acid oxidation, which can promote insulin resistance.
Additionally, some hepatokines influence insulin secretion by the pancreas, which can independently affect peripheral tissue
glucose uptake and metabolism.

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adipocyte lipolysis through a process that is dependent studies, liver-specific overexpression of DPP impairs
on its C-terminal fibrinogen-like domain (), and it whole-body glucose tolerance in high-fat–fed mice,
suppresses lipoprotein lipase activity via its N-terminal effects that are linked to reduced circulating GLP- ().
coiled-coil domain (). This increases plasma free fatty DPP is likely to directly affect metabolism in peripheral
acids and triglycerides, which is associated with ectopic tissues, as treatment of primary hepatocytes, adipocytes,
lipid accumulation in liver and skeletal muscle (, , and skeletal myotubes with recombinant DPP impairs
) and is highlighted by dyslipidemia in mice with insulin sensitivity (, ). However, a receptor for
liver-specific overexpression of Angptl (). Consistent DPP has not yet been identified. DPP also drives liver
with these functions, individuals heterozygous or ho- steatosis, most likely by increasing fatty acid uptake and
mozygous for the loss-of-function Angptl variant EK storage in hepatocytes (). In agreement with these
have significantly lower fasting plasma triglyceride levels observations, genetic ablation () or administration of
() whereas Angptl2/2 mice have increased VLDL oral DPP inhibitors such as vildagliptin () or
clearance (). Free fatty acids upregulate Angptl sitagliptin () improves both hepatic steatosis and
expression via peroxisome proliferator-activated re- glucose tolerance, further highlighting the systemic and
ceptor (PPAR)a activation in the liver and PPARg in autocrine/paracrine actions of DPP.
adipose tissue (), demonstrating the likelihood of a
feed-forward loop whereby lipid oversupply drives Ectodysplasin A
Angptl expression and high ANGPTL levels further Ectodysplasin A is a newly discovered hepatokine that
drive dyslipidemia. Such regulation would be clinically is associated with obesity and insulin resistance ().
unfavorable for PPAR agonists, which are used as Liver and serum ectodysplasin A levels are increased
antidiabetic and lipid-lowering agents. Insulin sup- in high-fat–fed mice and mice with genetic obesity
presses hepatic Angptl expression; however, this (i.e., leptin receptor–deficient db/db mice), and liver
mechanism is likely to be impaired in insulin-resistant ectodysplasin A mRNA levels increase with steatosis
states (). severity and correlate with a reduction in whole-body
The role of ANGPTL on insulin action and insulin action in humans (). In parallel with these
glycemic control is controversial. Although mice with findings, treatment of CC skeletal myotubes or
ANGPTL overexpression have severe hepatic stea- whole-body overexpression of ectodysplasin A in mice
tosis, they exhibit improvements in hepatic and sys- induces muscle insulin resistance in association with
temic insulin sensitivity (, ). In agreement, ANGPTL activation of c-Jun N-terminal kinase (JNK), and these
increases insulin-mediated inhibition of gluconeogene- effects were reversed upon partial silencing of ecto-
sis and decreases hepatic glucose production in primary dysplasin A in mice () (Fig. ). Notably, ectodys-
hepatocytes, and in humans ANGPTL levels correlate plasin A did not affect hepatic insulin action or other
positively with insulin sensitivity (). In contrast, parameters of energy homeostasis, pointing to a direct
reducing plasma ANGPTL via genetic deletion in liver-to-muscle crosstalk. Additional work is required
mice reduces blood lipids, reduces ectopic lipid ac- to determine the role of ectodysplasin on lipid
cumulation in liver and muscle, enhances insulin metabolism and confirm the relevance of this protein
signaling, and improves glycemic control (, , ), in NAFLD and type  diabetes.
and anti-ANGPTL antibody therapy in obese and
diabetic mice recapitulates this favorable metabolic Fetuin A
phenotype (). Further studies are clearly required Fetuin A (also known as a--HS-glycoprotein) is a
to fully understand the discrepancy in these disparate liver-secreted glycoprotein encoded by the ASHG
findings and to ascertain the potential of ANGPTL gene. Fetuin A is positively associated with circulating
therapeutic applications in dyslipidemia and glycemic triglycerides, the severity of NAFLD (, ), and
control. insulin resistance (, ) in rodents and humans. In
this regard, lipid oversupply induces ER stress, which
Dipeptidyl peptidase-4 activates extracellular signal–regulated kinase (ERK)/
Dipeptidyl peptidase- (DPP) is a ubiquitous serine and JNK to drive fetuin A production (). The he-
protease secreted by the liver that rapidly inactivates the patic expression and secretion of fetuin A is also
circulating incretin hormones glucagon-like peptide regulated by F-box and WD repeat domain-containing
(GLP)- and gastric inhibitory peptide (GIP) ().  (FBXW), a ubiquitin protein ligase that degrades
Incretins are important regulators of whole-body glu- fetuin A. FBXW is suppressed in obese mice and in
cose homeostasis, as GLP- and GIP promote insulin humans with obesity in parallel with increased fetuin
secretion and suppress glucagon secretion, resulting in A levels (). Fetuin A induces insulin resistance
peripheral glucose uptake and reduced hepatic glucose by several mechanisms (, –) (Fig. ). Fetuin
output (). Individuals with NAFLD and insulin re- A inhibits insulin receptor tyrosine kinase activity,
sistance have elevated plasma DPP activity (), which resulting in lower autophosphorylation and impaired
is consistent with lower GLP and GIP levels in the insulin signaling (). Fetuin A also acts as an en-
blood of these individuals (). Consistent with human dogenous ligand for Toll-like receptor (TLR), which
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Figure 2. The influence of hepatokines on insulin resistance in skeletal muscle or adipose tissue. Hepatokines target pathways
involved in regulating insulin action. Fetuin A (in the presence of palmitate) and RBP4 can activate TLR4 and result in JNK phosphorylation,
greater serine phosphorylation of IRS1, and suppression of insulin signaling and GLUT4 trafficking to the sarcolemma. Fetuin A and SeP can
directly inhibit the insulin receptor, resulting in lower insulin signaling and GLUT4 trafficking. Fetuin A can promote ER stress through
unknown mechanisms, resulting in greater JNK activation and impaired insulin signaling. Follistatin, HFREP1, LECT2, PEDF, and ectodysplasin
are also implicated in impairing insulin signaling secondary to activation of JNK; however, the upstream signaling is unresolved.
enables saturated free fatty acids to activate TLR humans (). This indicates that fetuin B’s primary
signaling to induce insulin resistance (). This fetuin function is the suppression of glucose effectiveness
A/free fatty acid interaction predicts the development (), which refers to the ability of glucose to promote
of insulin resistance in humans (). In the pancreas, its own disposal, independently of insulin (Fig. ). This
fetuin A signals to b-cells and impairs glucose sensing process is at least as important as insulin for glucose
(), which results in impaired insulin secretion (, clearance, accounting for ~% of an oral glucose
) in response to inflammatory processes, including tolerance test in normal individuals and ~% in
TLR, JNK, and nuclear factor kB (NF-kB) activation insulin-resistant individuals with obesity (). Ad-
and the accumulation of lipotoxic lipids (, ). ditionally, there is evidence that fetuin B impairs first-
Mice with global fetuin A deletion show improved phase glucose-stimulated insulin secretion (), signifying
insulin sensitivity and are resistant to diet-induced a role in b-cell function. The importance of fetuin B in
obesity (, ), highlighting the likely therapeutic NAFLD-induced insulin resistance is confirmed by
potential of fetuin A antagonists. studies showing that short hairpin RNA suppression
of liver fetuin B protein and reduced fetuin B secretion
Fetuin B improve glycemic control in obese, insulin-resistant
Fetuin B is encoded by the FETUB gene and shares mice ().
% homology with fetuin A. Fetuin B is increased in
patients with NAFLD (, , , ), type  di- Fibroblast growth factor 21
abetes (, ), and gestational diabetes (, ), Fibroblast growth factor (FGF) regulates systemic
and it correlates positively with insulin resistance lipid metabolism in response to diet, exercise, and cold
(). Although administration of fetuin B induces exposure (, ), and its role in metabolism has
insulin resistance in myotubes and hepatocytes in been extensively reviewed (). FGF expression is
vitro, administration of fetuin B in lean mice caused increased by activation of PPARa (), and consistent
whole-body glucose intolerance but not insulin re- with this finding, humans with NAFLD have increased
sistance (), observations that were recapitulated in circulating FGF levels (, ). This may be a

REVIEW
compensatory response designed to limit the impact of NAFLD and systemic insulin resistance. HFREP is
lipotoxic stress, as FGF reduces adipose tissue li- elevated in human NAFLD () and NASH (), and
polysis (, ), increases fatty acid oxidation, lowers circulating concentrations correlate positively with
hepatic lipids such as diacylglycerol, enhances insulin plasma glucose levels and insulin resistance (). In
sensitivity, and improves glycemic control (, , mice, high-fat feeding promotes liver HFREP ex-
). FGF also reduces hepatic VLDL secretion and pression and NAFLD (), suggesting that elevated
accelerates VLDL disposal in both white and brown circulating lipids induce hepatic HFREP expression.
adipose tissue via coordinated upregulation of CD In this context, the fatty acid palmitate (C:) dose-
and lipoprotein lipase (). The importance of FGF dependently increases HFREP expression in hepa-
is highlighted in mouse studies where the deletion of tocytes (). Lipid-dependent HFREP expression is
Fgf, its receptor FGF receptor-c, or the coreceptor mediated by ER stress and the resultant activation of
b-klotho, results in greater adiposity, hepatic steatosis, the P and CCAAT/enhancer-binding protein b in
and liver insulin resistance, increased hepatic glucose hepatocytes, and pharmacological blockade of this
production, and hyperglycemia (). Finally, FGF pathway blunts HFREP expression and partially re-
promotes pancreatic b-cell function and insulin se- stores insulin action (). This provides a plausible
cretion (). It is for these reasons that FGF has mechanism for NAFLD-induced HFREP production,
emerged as a therapeutic agent for the treatment of given that ER stress is elevated in humans with
type  diabetes and the metabolic syndrome (), conditions characterized by dyslipidemia such as
although FGF analogs have failed to lower blood NAFLD (), diabetes (), and obesity ().
glucose in humans. Moreover, HFREP promotes lipogenesis through
ERK/ activation (), indicating the presence of a
Follistatin feed-forward mechanism that drives NAFLD. HFREP
Follistatin is a member of the TGFb family and was has also been shown to cause insulin resistance in
originally recognized for its inhibitory effect on FSH immortalized CC myotubes and skeletal muscle ex
production in the pituitary () and, later, suppres- vivo (), which is mediated by decreased 9-AMP–
sion of myostatin to support skeletal muscle growth, activated protein kinase (AMPK) phosphorylation
which demonstrated actions outside of the re- and enhanced JNK activation in a process dependent
productive system (). Follistatin is increased in on epidermal growth factor receptor and FOXO
serum of individuals with NAFLD () and type  phosphorylation (). Administration of recombinant
diabetes (), potentially through forkhead box O HFREP or genetic overexpression of HFREP causes
(FOXO)–mediated transcriptional activation (). liver and skeletal muscle insulin resistance (), whereas
In contrast, weight loss following bariatric surgery deletion of liver HFREP protects against diet-induced
leads to a reduction in serum follistatin, which is insulin resistance in mice () (Fig. ). Reducing cir-
accompanied by improvements in insulin sensitivity culating HFREP could therefore be a viable approach
and glycemic control (, ). It remains to be for insulin resistance.
determined whether the decrease in serum follistatin
is a direct mediator of the improvements in glycemic High-mobility group box 1 protein
control. However, it is known that follistatin promotes Sterile inflammation caused by free fatty acids,
proinflammatory cytokine expression, such as IL-b, chemokines, and cytokines stimulates the release of
that is implicated in fibrosis progression (, ) and endogenous molecules termed damage-associated
the development of insulin resistance in adipose tissue molecular patterns, and these molecules can activate
() and skeletal muscle (). Similarly, follistatin TLR signaling in a variety of cell types that promote
overexpression in isolated hepatocytes or livers of mice inflammatory responses. High-mobility group box 
impairs signaling in white adipose tissue, insulin- protein (HMGB) was originally discovered as a
mediated suppression of hepatic glucose production, protein that binds to nucleosomes to stabilize DNA
and whole-body glucose tolerance, whereas follistatin structure and modulate transcription (), but more
knockdown improves insulin sensitivity () (Fig. ). recently it has been shown to be secreted from he-
Taken together, these studies provide evidence that patocytes (). HMGB expression and secretion are
follistatin is increased with NAFLD and can pro- increased in NAFLD, and this process is mediated by
mote inflammation, insulin resistance, and glucose increased free fatty acid availability (). The secreted
intolerance. HMGB activates TLR signaling and the resultant
NF-kB activation drives inflammation in neighboring
Hepatocyte-derived fibrinogen-related protein 1 hepatocytes. Given that TLR activation dampens
Hepatocyte-derived fibrinogen-related protein  insulin signaling (), it is possible that HMGB–
(HFREP), also referred to as hepassocin or fibrinogen- TLR signaling may contribute to insulin resistance
like protein , is secreted by hepatocytes and is known in NAFLD, although this requires formal testing.
to promote cell growth and proliferation (–). Blocking HMGB reduces lipotoxic effects in hepa-
More recently, HFREP has been implicated in tocytes () and protects against NAFLD progression
REVIEW
in rats (, ), which supports a prominent autocrine/ via its interaction with adipose triglyceride lipase
paracrine role. Whether the pathogenic effects of (ATGL), the rate-limiting enzyme for triglyceride
HMGB extend beyond the liver in humans is hydrolysis, and this coincides with increased ceramide
questionable, as HMGB levels are not associated with and diacylglycerol accumulation in liver and muscle
histological severity in NAFLD (). (, , , ). Neutralizing PEDF with monoclonal
antibodies reverses these effects (). Whereas circu-
Inhibin bE lating PEDF correlates with hepatic steatosis and in-
The hepatokine inhibin bE is a member of the TGFb sulin resistance, liver-specific overexpression of Pedf
family and is positively associated with body mass reverses hepatic lipid accumulation (), which likely
index and insulin resistance in rodents (, ) and reflects higher intrahepatic lipolysis, and it aligns with
humans (). Knockdown of hepatic inhibin bE lower NASH development (, ). Taken together,
using small interfering RNA attenuates fat mass gain this suggests that the increased production of PEDF
in parallel with greater whole-body fat oxidation in with NAFLD is directed toward secretion and not
obese db/db mice (); however, no overt metabolic retained within the liver, where it promotes insulin
phenotype was reported in Inhbe knockout mice (). resistance and dyslipidemia.
Additional work is needed to determine whether in-
hibin bE indeed increases fat oxidation and whether Retinol binding protein 4
blocking inhibin bE’s actions has therapeutic utility Retinol binding protein  (RBP) is a liver and ad-
for NAFLD and perhaps obesity. ipose tissue secreted protein that transports vitamin
A in the form of retinol (). Serum RBP levels are
Leukocyte cell–derived chemotaxin 2 increased with NAFLD (, ), insulin resistance
Leukocyte cell–derived chemotaxin  (LECT) is a (), and in type  diabetes (), and reduced with
-kDa hepatokine originally described as chemotactic diet-induced weight loss (), bariatric surgery
for neutrophils (). LECT has since been impli- (), and exercise (). Although these findings in
cated in NAFLD (, ) and insulin sensitivity (, humans suggest a potential role for RBP in reducing
), and circulating LECT expression is positively insulin action, direct examination of RBP effects
correlated with body weight and insulin resistance in in mice are equivocal. RBP overexpression causes
humans (). Studies in mice show that whole-body inflammation and insulin resistance in mouse adi- “…ketone bodies signal to
deletion of Lect enhances insulin-stimulated AKT pose tissue due to activation of JNK and TLR peripheral tissues and the
phosphorylation in skeletal muscle, whereas admin- signaling (), and genetic deletion of Rbp enhances central nervous system to
istration of recombinant LECT activates JNK () insulin sensitivity () (Fig. ). However, in a recent regulate metabolism.”
and inhibits insulin signaling via increased serine study where RBP was overexpressed specifically in
phosphorylation of IRS () (Fig. ). Interestingly, the liver of mice, glycemic control was not affected
pharmacological inhibition of DPP improves glucose despite significant increases in circulating RBP levels
metabolism in mice in parallel with a reduction in (). In light of these conflicting data, additional
hepatic LECT protein content, and this occurs via research is warranted to determine RBP’s role in the
activation of AMPK and suppression of JNK activity pathogenesis of NAFLD and type  diabetes.
(). Thus, DPP may regulate LECT expression,
indicating likely cross-talk between hepatokines in Selenoprotein P
NAFLD. Circulating selenoprotein P (SeP) levels are positively
correlated with type  diabetes (), insulin resistance,
Pigment epithelium-derived factor and blood glucose levels in humans (–), which
Pigment epithelium–derived factor (PEDF) is a agrees with studies in mice reporting increased liver
-kDa noninhibitory serine protease originally found expression and secretion of SeP in response to high-fat
to be secreted by retinal epithelial cells, but it is also feeding (), NAFLD (), and type  diabetes ().
highly expressed in, and secreted by, liver and adipose SeP expression and secretion are increased in response
tissue (). Liver PEDF expression () and circu- to ER stress and JNK activation, subsequent to TLR
lating PEDF levels (–) are increased in humans stimulation (). Moreover, activation of AMPK via
with obesity, insulin resistance, and NAFLD, and it is the anti-inflammatory drug salsalate or the insulin-
reduced with weight loss (). PEDF is implicated in sensitizing drug metformin protects against ER stress
the development of insulin resistance and glucose and SeP production (). Taken together, this links
intolerance in mice (). PEDF increases JNK and proinflammatory and/or dyslipidemic states to in-
ERK/ activity in skeletal muscle and liver, as well creased SeP expression.
as NF-kB activity in adipocytes, which corresponds Consistent with a role in metabolic disease, acute
with reduced insulin signal transduction (, ) administration of recombinant SeP causes insulin
(Fig. ). Increasing plasma PEDF by administration of resistance in mice (). In vitro, SeP administration
recombinant PEDF or overexpression of Pedf in ad- impairs insulin receptor phosphorylation in HepG
ipose tissue of mice increases adipose tissue lipolysis hepatocyte-like cells, suggesting direct inhibition of

REVIEW
autophosphorylation at this proximal step of insulin by the improvements in systemic metabolism rather
signaling () (Fig. ). Additionally, SeP impairs than direct actions targeting proinflammatory, profi-
glucose-stimulated insulin secretion in pancreatic brotic, or insulin signaling pathways. Future work
b-cells, effects that are reversed by monoclonal anti- including the identification of the putative TSK re-
body neutralization of circulating SeP (). Genetic ceptor is required to determine the role of TSK in lipid
deletion and RNA interference–mediated knockdown metabolism and insulin signaling in peripheral tissues.
of SeP improves systemic insulin sensitivity and glu-
cose tolerance (), whereas SeP-neutralizing anti- Hepatocyte exosomes and protein secretion
bodies improve insulin secretion and glycemic control Exosomes are emerging as an important mode of
in diabetic mice (), collectively highlighting the intercellular and intertissue communication. Proteo-
potential therapeutic utility of this hepatokine. mic analysis of exosomes derived from rat primary
hepatocytes identified ~ proteins, some of
Sex hormone binding globulin which are also denoted as classically secreted hep-
Sex hormone binding globulin (SHBG) is best known atokines (e.g., DPP). Bioinformatic analysis predicts
as a transporter of sex steroids (, ). Liver () that these hepatocyte-derived exosomal proteins are
and serum () SHBG levels are lower in individuals implicated in intracellular transport, lipid metabolism,
with hepatic steatosis when compared with individuals carbohydrate metabolism, metabolite availability, and
with no adverse liver pathology, and plasma SHBG protein turnover (). Although the influence of
negatively predicts insulin resistance and hyperinsulinemia NAFLD or NASH on liver-secreted exosomes is
(–). This is accompanied by lower hepatic SHBG poorly understood, in vitro studies showed that pal-
content and lower expression of the transcription factor mitate exposure increases exosome/extracellular vesicle
hepatocyte nuclear factor a, a key transcriptional reg- secretion (–), and that these exosomes contained
ulator of SHBG (). Additionally, low circulating SHBG a greater proportion of proteins involved in regulating
is independently associated with obesity, and weight loss fibrosis (i.e., a-SMA, TGFb, Cola) (). These
following bariatric surgery increases circulating SHBG exosomes were found to communicate with “healthy”
levels (). Collectively, these data describe a clear as- hepatocytes to promote the progression of fibrosis
sociation between obesity, NAFLD, insulin resistance, and (–), suggesting a potential autocrine effect of
lower SHBG levels in liver and blood. exosomes in liver disease. However, this is very much an
The lower expression of SHBG in NAFLD may emerging field, and the importance of liver-derived
occur secondary to inflammation, as an increase in exosomes in regulating cell metabolism and influenc-
TNFa in response to JNK and NF-kB activation re- ing whole-body glucose homeostasis is currently un-
duced SHBG production in HepG cells (). Given known. Future work should examine how liver disease
that insulin promotes SHBG production in vitro (), affects the protein composition in liver-secreted exo-
and people with type  diabetes have a stronger re- somes, and whether these exosomes are important
lationship between insulin levels and SHBG than do mediators of insulin resistance.
those with type  diabetes (), it is possible that
hepatic insulin resistance could precede a reduction in Summary
SHBG and exacerbate lipid accumulation. This notion Hepatokines clearly exert pleiotropic effects on lipid
is at least partially supported by the finding that and glucose metabolism and insulin action, and their
resveratrol, a polyphenol that improves insulin sen- secretion is impacted by NAFLD (Table ). Although
sitivity, also increases SHBG levels in mice (). The there has been one comprehensive examination of the
mechanisms underpinning the effects of SHBG on hepatocyte protein secretome (), which demon-
glycemic control are unknown. With respect to lipid strates marked changes in response to simple steatosis,
metabolism, overexpression of SHBG suppresses li- rapid developments in mass spectrometry now
pogenesis (, ) that could reduce hepatic steatosis. permit a deeper examination of cell/tissue secretomes,
enabling more detailed understanding of the breadth
Tsukushi of protein secretion during the progression of NAFL to
Tsukushi (TSK) is a highly conserved proteoglycan in NASH. Performing such experiments in human liver
mammals and a newly discovered hepatokine that is tissues will be important in driving our understanding
increased in rodent obesity () and NASH (). of hepatokines in physiology and NAFLD-related
Studies in Tsk-null mice highlight an important role comorbidities and, by extension, the identification
for TSK in regulating energy balance under obesogenic of therapeutic targets to treat cardiometabolic diseases.
conditions. TSK is induced in response to increases in Such studies will also be important for identifying
energy expenditure, which blunts sympathetic outflow novel biomarkers that could be used in conjunction
and innervation of adipose tissue, thereby reducing with readily available clinical parameters to identify
thermogenesis and energy expenditure (). Ablation the presence and staging of NAFLD/NASH with
of TSK also prevents diet-induced NASH and whole- higher sensitivity and specificity than current risk-
body insulin resistance (), which may be mediated stratification algorithms used in routine clinical care.
REVIEW
Metabolite secretion, NAFLD, and oxidative stress (), a well-documented mediator of

insulin resistance insulin resistance (). Second, b-hydroxybutyrate
The liver plays critical roles in regulating systemic directly modulates lysine residues on histones via a
glucose and lipid metabolism, processes that have been process known as lysine b-hydroxybutyrylation,
extensively reviewed in the context of NAFLD (). leading to activation of starvation-regulated meta-
Glucose and VLDL aside, liver-derived major me- bolic pathways, including amino acid catabolism,
tabolite classes, including lipoproteins, ketones, acyl- PPAR signaling, and oxidative phosphorylation ().
carnitines, and bile acids, appear to transduce specific Although correlative, HDAC inhibition is reported with
metabolic signals; however, much of the literature on the consumption of ketogenic diets, with subsequent
this topic remains correlative and circumstantial with activation of PPARa and the expected sequalae of
regard to their endocrine functions. This mode of increased expression of lipid metabolism genes (),
intertissue communication is discussed below with this greater hepatic fatty acid oxidation and plasma tri-
caveat in mind. glyceride clearance, and FGF production (, ).
Thus, b-hydroxybutyrate links changes in metabolite-
Ketones directed histone modifications to changes in cellular
Ketone bodies such as acetone, acetoacetate, and metabolism.
b-hydroxybutyrate are produced in the liver using Although b-hydroxybutyrate is commonly used in
b-oxidation–derived acetyl-CoA as substrate, and they metabolic studies to represent “ketones,” acetoacetate
are then secreted from the liver for transport to other constitutes % to % of the total hepatic ketone
peripheral tissues. Upon their uptake by peripheral body pool (, ) and is thereby a significant source
tissues, ketone bodies are converted back to acetyl- of acetyl-CoA and a potential signaling molecule.
CoA, which provides substrate for energy production Acetoacetate can inhibit glucose uptake in skeletal
through the tricarboxylic acid (TCA) cycle and ox- muscle and heart (, ), although others show no
idative phosphorylation. The excess acetyl-CoA also effect (). Recent work has shown that hepatocyte-
increases the capacity for protein acetylation, par- secreted acetoacetate, but not b-hydroxybutyrate,
ticularly of mitochondrial proteins, which regulates ameliorates diet-induced hepatic fibrosis (), but
the activity of transcription factors and transcrip- these studies did not assess metabolism, and a better
“Increased circulating
tional coactivators such as FOXO, PPARg coac- understanding of acetoacetate roles in metabolism is
ceramide and/or ceramide
tivator a (PGCa), and PPARg, all of which play needed. Similarly, another ketone, acetone, can be accumulation in rodents
critical roles in regulating the expression of metabolic taken up by tissues but its effects on glycemic control induces inflammation and
genes, particularly in response to changes in nutrient and insulin sensitivity are unknown. Further detailed insulin resistance.”
availability (, ). In this regard, ketogenesis is information on ketones and metabolism is available
important when carbohydrate is limiting, including elsewhere ().
starvation and with the consumption of extremely The role of ketones in regulating insulin action and
low-carbohydrate diets, which are often referred to as glycemic control is equivocal (–). These con-
“ketogenic” diets (, ). Ketone bodies conflicting findings result from discrepancies in study
tribute up to % of total energy expenditure under designs, the composition of ketogenic diets, the like-
these conditions (, ). lihood of “positive” and “negative” responders to ke-
Moving beyond their direct role as an energy togenic dietary intervention, the duration of the
substrate, ketone bodies signal to peripheral tissues ketogenic diet, and the myriad of “off-target” changes
and the central nervous system to regulate metab- that accompany ketogenic diet consumption.
olism. Ketones can cross the blood–brain barrier and Ketone bodies in NAFLD. Hepatic ketogen-
are sensed in the hypothalamus to stimulate food esis and plasma b-hydroxybutyrate are reportedly
intake by increasing the expression of the orexigenic increased (, ), unchanged (–), or decreased
neuropeptides Npy and Agrp () and through the (, ) in rodents and humans with NAFLD. There
potentiation of hypothalamic leptin and insulin sig- is similar uncertainty in NASH, with reports of higher
naling () (Fig. ). Such signaling is associated with (, ) or lower levels () of circulating ketone
reduced adiposity and improved systemic insulin bodies compared with individuals with steatosis or no
sensitivity (). In the periphery, b-hydroxybutyrate liver pathology. Future studies are required to clarify
regulates lipid metabolism in adipocytes via activa- this ambiguity and to also identify the potential links
tion of hydroxy-carboxylic acid receptor  (HCA, between specific ketones and insulin action.
GPRA), which sequentially decreases adenylyl
cyclase activity, protein kinase A activity, and lipolysis Lipoproteins
(, ). b-Hydroxybutyrate is also implicated in the The liver secretes lipids primarily within VLDLs, but
longer-term regulation of metabolism by modifying also within extracellular vesicles. Although most lipids
histones through two distinct epigenetic processes. within VLDLs are triglycerides (~%), VLDLs also
First, b-hydroxybutyrate inhibits class I histone deace- contain cholesterol and cholesterol esters (~%)
tylase (HDAC) (), which is associated with reduced and phospholipids (~%), with most being :-

REVIEW
Figure 3. Hepatic metabolite secretion. Different pathways for metabolite secretion are color-coded. Fatty acids (FA) are taken up
by hepatocytes and can be converted to acylcarnitine for oxidation within the mitochondria. These acylcarnitines can be secreted
from the liver and induce insulin resistance in peripheral tissues (green). Ketone bodies are produced during mitochondrial fatty
acid oxidation and can be secreted from hepatocytes, affecting oxidative metabolism, and they may affect insulin sensitivity in
peripheral tissues (orange). The liver plays a significant role in lipoprotein metabolism by taking up chylomicron remnants from the
circulation (blue) and by secreting VLDLs that transport triglycerides (and other lipids) to peripheral tissues (yellow). Cholesterol
synthesized within the liver or taken up as part lipoproteins can be converted to bile acids, which are secreted and affect intestinal
lipid absorption and bile flow, as well as peripheral metabolism through activation of various receptors (blue). Lastly, the liver
secretes exosomes that carry thousands of metabolites, including ceramide and LPC, that were shown to lead to stellate cell
activation and fibrosis in a paracrine manner (red). Changes in those pathways with NAFLD are shown with red arrows (↑ increased,
↓ decreased with NAFLD, ? unknown or controversial). HSC, hepatic stellate cell; TAG, triacylglycerol.
containing phosphatidylethanolamine (). Addi- availability, as shown experimentally by coinfusing

tionally, % to % of liver sphingolipids, mainly Intralipid (triglyceride emulsion) and heparin
ceramide and free sphingosine, can be released as (lipoprotein lipase activator) (, ) (Fig. ).
components of VLDLs (). Increased circulating VLDLs, and thereby tri-
Fatty acids are cleaved from triglyceride con- glycerides, is associated with hepatic steatosis,
tained within VLDLs by lipoprotein lipase that is obesity, and insulin resistance (, ). Once
localized to the surface of endothelial cells in depleted from triglyceride, lipoprotein particles are
capillaries and are transported into cells residing in enriched in cholesterol and cholesterol esters to
close proximity or carried in the blood bound form intermediate-density lipoproteins or low-
to albumin. Increasing VLDL-triacylglycerol se- density lipoproteins (LDLs). Insulin resistance in
cretion and delivery to tissues can cause periph- humans is characterized by high levels of plasma
eral insulin resistance by increasing fatty acid cholesterol esters (), and high circulating cholesterol
REVIEW
levels are associated with reduced insulin secretion, and/or ceramide administration in rodents induces
effects that can be normalized with cholesterol depletion inflammation and insulin resistance, particularly in
(). Cholesterol accumulation within the plasma skeletal muscle (, –), whereas a reduction
membrane of skeletal muscle is associated with insulin in liver and plasma ceramide after weight loss is
resistance secondary to reduced GLUT insertion associated with reduced inflammation and im-
within the membrane (, ). These studies suggest proved insulin sensitivity (, , ). Addi-
that circulating cholesterol (liver derived or from other tionally, these patients showed reductions in
sources) has a negative impact on glycaemic control. We plasma cholesterol, triglycerides, LDLs, and free
are not aware of any studies assessing the direct impact fatty acids (), increased ketone bodies and
of liver-derived VLDL/LDL-associated cholesterol on acylcarnitines, and reduced levels of branched-
glucose metabolism. However, as the liver is a major site chain amino acids and (lyso)glycerophospholipids
of endogenous cholesterol synthesis and secretion (), (), suggesting that reductions in plasma ceramide
most peripheral effects are most likely related to liver- is one of many changes that mediate systemic meta-
derived cholesterol. bolic improvements with weight loss. Similarly,
Intracellular ceramide accumulation causes insulin induction of hepatic ceramide degradation through
resistance (), and circulating ceramides appear to increased expression of acid ceramidase within the
induce similar effects. Ceramides contained within liver and subsequent reductions in circulating
LDLs are transferred to the plasma membrane of ceramide are associated with improvements in
skeletal muscle, which leads to a reduction in insulin- hepatic steatosis and systemic insulin sensitivity
stimulated GLUT translocation (). LDL ceramides (, ).
also induce inflammation in macrophages (), per-
haps via a TLR-dependent mechanism, which can in Acylcarnitines
turn induce insulin resistance in peripheral tissues (). Acylcarnitines are generated through coupling of
Additionally, treatment of macrophages with VLDLs acyl-CoA to carnitine for import into the mito-
increases macrophage ceramide content and promotes chondrial matrix. Once inside the mitochondria,
an M-like macrophage polarization, leading to adipose carnitine and acyl-CoA are regenerated and acyl-
tissue inflammation and insulin resistance in diet- CoA is oxidized through b-oxidation. Acylcarni-
induced obese mice (). tines are an important energy source within the
Lipoproteins in NAFLD and insulin re- mitochondria, and they are also secreted into the
sistance. Hepatic steatosis is associated with in- circulation (), either directly into the blood
creased secretion of VLDLs and increased plasma through the acylcarnitine transporter SLCA
triglycerides (, ), and patients with NAFLD () or within extracellular vesicles (, ). The
have a reduced capacity for insulin-mediated suppres- liver (, ), but not skeletal muscle (, ),
sion of VLDL secretion (), which may contribute to is the major source of circulating acylcarnitine and
the insulin resistance and glucose intolerance that is this is most pronounced with fasting (). Acyl-
commonly associated with NAFLD (, ). Fur- carnitines can provide up to % of the circulating
thermore, increased VLDL secretion is associated with carbon product from fatty acids () and are taken
inflammation, particularly increased TNFa production up by skeletal muscle, heart, and brown adipose
(), and increases in TNFa can further drive hepatic tissue (, ). Acylcarnitine accumulation in
VLDL secretion () and insulin resistance (). muscle has been linked to skeletal muscle insulin
VLDL and LDL particles carry ceramide (, resistance (), which is thought to result as a
), and hepatic ceramide secretion is increased in product of a mismatch between fatty acid oxidation
the presence of lipid oversupply (, ). Fur- and TCA flux, resulting in mitochondrial stress and
thermore, ceramide transported in LDLs is in- reactive oxygen species production () (Fig. ).
creased in the plasma of individuals with obesity Some studies demonstrate increased plasma acyl-
with type  diabetes and correlates with insulin carnitines in humans with insulin resistance (,
resistance (). The liver is the major contributor ), and treating CC myotubes with acylcar-
to circulating ceramide levels (), and liver nitine modestly impairs insulin signaling ().
ceramide synthesis is highly dependent on fatty acid Whether circulating acylcarnitines impair systemic
availability (), linking dysregulated adipose insulin action and glucose homeostasis is ques-
tissue lipolysis to liver-derived ceramide in the tionable because increasing plasma acylcarnitines
circulation and NAFLD. Increased ceramide se- via g-butyrobetaine supplementation in mice ()
cretion in conditions of hepatic steatosis/hepatic or carnitine supplementation in rats () does not
lipid oversupply may reflect an attempt by the liver affect glucose homeostasis. In addition to their
to protect itself from the deleterious consequences potential role in (dys)regulating insulin action,
of intracellular ceramide accumulation (), al- acylcarnitines are taken up by pancreatic b-cells,
though there is presently no known ceramide leading to insulin depletion as a result of a com-
sensing mechanism. Increased circulating ceramide bination of diminished insulin refill and enhanced

REVIEW
insulin granule release (). Acylcarnitines acti- this area are contradicting. Most studies report
vate proinflammatory signaling in macrophages increases in liver and circulating bile acids with
(), and liver-derived acylcarnitines are a likely progressive NAFLD (–), and circulating bile
fuel source for brown fat thermogenesis during cold acids appear to be related to the metabolic phe-
exposure, suggesting a role for acylcarnitines in notype associated with NAFLD/NASH, especially
regulating energy homeostasis () (Fig. ). insulin resistance (). Further work is clearly
Acylcarnitines in NAFLD and insulin re- needed to bridge the gap between the un-
sistance. Plasma acylcarnitines have been reported derstanding of bile acid secretion and their met-
to be decreased in individuals with hepatic stea- abolic functions and influence on metabolic
tosis () and increased in patients with NASH diseases when considering the development of
(–), while others report acylcarnitine species- targeted therapies in NAFLD.
specific changes with NAFLD (). The increase in
NASH patients could be attributed to the down- Metabolite secretion in exosomes
regulation of carnitine palmitoyltransferase  (CPT) Most hepatic lipids are secreted within lipoprotein
and a subsequent decrease in mitochondrial fatty acid particles, and far less is known about the secretion of
entry and oxidation (). These reported differences hepatic lipids or other metabolites contained within
may relate to changes in mitochondrial b-oxidation extracellular vesicles, including exosomes. In humans,
with NAFLD progression (), as b-oxidation is ~% of total lipids found in serum are contained
reduced in livers with steatosis/NAFL (, ) and within lipoproteins (), suggesting that only a minor
increased in NASH (, ). The mechanisms component of circulating lipids (~%) are transported
underpinning NAFLD stage-specific differences in in extracellular vesicles (Fig. ). This relative low
lipid metabolism remain unresolved, and it would be abundance of lipids does not exclude a meaningful
interesting to assess how and why b-oxidation (and contribution of exosomal lipids as signaling molecules
subsequently acylcarnitine secretion) is altered with because exosomes can be targeted to specific cell/tissue
the progression of NAFL to NASH. At this point, types (). Liquid chromatography–tandem mass
it is difficult to reconcile any clear association be- spectrometry and other biochemical approaches have
tween NAFLD, acylcarnitines, and impaired glycemic identified many lipid species in exosomes [e.g., 
control. lipid species from  lipid classes (),  lipid
species from  lipid classes ()], reflecting a
Bile acids complex lipid composition. The most abundant lipid
Oxidation of cholesterol within the liver results in the classes found within exosomes are cholesterol, phos-
generation of bile acids, including cholic acid, che- pholipids, sphingolipids, and the mitochondrial lipid,
nodeoxycholic acid, and deoxycholic acid. In addi- cardiolipin (–). Although the lipid composition
tion to well-documented roles in intestinal lipid of exosomes generally resembles the lipid composi-
absorption and cholesterol metabolism (), bile tion of the cell of origin, more so than the exosomal
acids act as signaling molecules by activating the protein content (, ), certain lipids have been
nuclear receptors farnesoid X receptor, pregnane shown to be enriched within all exosomes, as discussed
X receptor, and vitamin D receptor, as well as below.
the G-protein–coupled receptor TGR, which are Little is known about the composition of liver-
expressed within and external to the enterohepatic derived exosomes, especially in NAFLD. Hepatocytes
system (). For the most part, bile acids induce secrete exosomes that carry ceramides and preferen-
favorable metabolic outcomes such as reduced he- tially fuse in a paracrine manner with hepatocytes
patic gluconeogenesis and improved glucose ho- (), and one study examined the composition of
meostasis through farnesoid X receptor (, ) immortalized Huh hepatocellular carcinoma cell
and pregnane X receptor activation (), as well as exosomes and showed that they are enriched in long-
increased energy expenditure in brown adipose tis- chain saturated free fatty acids (C: and C:),
sue, and improved glucose metabolism and insulin distearoyl phosphatidic acid [PA(:/:)], various
sensitivity through TGR () (Fig. ). Notably, phospholipids [particularly the phosphatidyl serine
these metabolic effects are unlikely to be mediated via PS(:/:)], lysophospholipids [e.g., lysophos-
direct actions in muscle and adipose tissue because of phatidylcholines (LPCs), lysophosphatidylserines,
the very low expression of these nuclear receptors in lysophosphatidylglycerol, lysophosphatidylinositol,
these tissues. Readers should refer to de Aguiar lysophosphatidylethanolamine), as well as a variety of
Vallim et al. () for an expansive review of bile acid sphingomyelin and cardiolipin species (). Notably,
effects on metabolism. the composition of human liver-derived exosomes and
Bile acids in NAFLD and insulin resistance. the role of the vast majority of exosomal lipids in
Detailed studies on the interaction between bile intercellular communication are unknown.
acids in the enterohepatic system and NAFLD are One of the more abundant lipids within hepatocyte-
limited, and the small number of investigations in derived exosomes is LPC (). The high LPC
REVIEW
Figure 4. Secretion of miRNA into the circulation. Secretion of miRNA encapsulated by (1) exosomes, (2) contained within HDL, or (3)
bound to argonaute 2 (Ago2), which is channeled through vesicle-associated membrane protein 3 (VAMP3) and synaptosomal-associated
protein 23 (SNAP23). DAG, diacylglycerol; LPC, lysophosphatidylcholine; TAG, triacylglycerol.
content within exosomes is not surprising, as LPC is abundance of amino acids and TCA intermediates
the most abundantly secreted phospholipid from the in exosomes, including acetate, citrate, pyruvate,
liver (). In addition to being found within exo- a-ketoglutarate, fumarate, and malate, and these can
somes, LPC is transported in the circulation bound to used as substrates by surrounding cells (–).
albumin and is the second most prevalent phospho- Exosomes in NAFLD and insulin resistance.
lipid in plasma (). Circulating LPCs activate Hepatic exosome secretion is increased with
GRP to enhance glucose-stimulated insulin se- NAFLD or lipid overload in vitro (, , ,
cretion () and to increase glucose uptake by in- ). The increase in exosome release with lipid
creasing GLUT translocation (, ), resulting overload is mediated by ER stress (), particularly
in lower blood glucose levels in mice with type  through IRE/XBP signaling (). These lipid
diabetes (). In humans, plasma LPC (and “overloaded” hepatocytes are enriched in C:
lysophosphatidylcholine/alkyl-phosphatidylcholine) ceramide, and they are packaged into exosomes in
levels are reduced in individuals with insulin resistance, either an IRE/XBP-dependent manner through
independent of obesity (), indicating that LPC se- ER stress-induced upregulation of the sphingolipid
cretion may be increased to protect against the insulin biosynthesis enzyme serine C-palmitoyltransferase
resistance associated with NAFLD. Irrespective, it re- (SPT) (), or through the activity of StAR-
mains uncertain as to how LPCs contained within related lipid transfer domain  (STARD), a
exosomes or other extracellular vesicles can be transferred ceramide transport protein (). Increased exo-
in meaningful quantities to impact cell functions in vivo. somal C: ceramide is also reported in mice and
The composition of nonlipid metabolites con- humans with NASH (); however, direct secre-
tained within liver-derived exosomes is not described. tion from the liver was not assessed in this study,
Metabolomic examination in other cells report high and the exosome source was not verified. Ceramides

REVIEW
stimulate exosome secretion (–), and hepatocyte- has been hindered by the inability to deliver lipids in
derived exosomes preferentially accumulate in stellate cells aqueous environments (e.g., blood, culture medium)
and hepatocytes, where they can promote stellate cell in a reproducible, physiologically relevant manner, and
activation and exacerbate liver fibrosis (, , ). This new technologies are urgently required to move this
raises the intriguing possibility that exosomal ceramides field forward.
promote NALFD progression to NASH through paracrine
interactions (, ). miRNA secretion
LPCs are present in hepatocyte-derived exosomes
(), but changes with NAFLD are currently un- miRNAs and intracellular metabolism
known. Patients with NAFLD show reductions in a miRNAs are noncoding RNAs of ~ nucleotides
variety of serum LPC and phosphatidylcholine that regulate gene expression by binding to the 9
species (–), which is related to increased gene untranslated region of mRNAs to repress translation
expression of proteins involved in LPC degradation or guide mRNAs for degradation in lysosomes ().
(). Interestingly, greater abundance of plasma miRNAs typically target mRNAs transcribed from
LPC-: can distinguish insulin-sensitive from insulin- gene clusters rather than single genes, which facili-
resistant NAFL patients, providing potential diagnostic tates critical roles in fundamental biological pro-
value and further supporting an insulin sensitizing role cesses, including cell proliferation, differentiation,
for LPCs (). and apoptosis. Intracellular accumulation of specific
miRNAs can regulate diverse metabolic functions
Summary in a variety of tissues, including skeletal muscle in-
Many studies in mice and humans have demonstrated sulin action, insulin secretion from pancreatic b-cells,
that several liver-derived lipids and metabolites can and adipocyte lipolysis (, ), thereby impli-
serve as signaling molecules to regulate insulin action cating miRNAs in the pathophysiology of metabolic
and other metabolic processes. Recent advances in diseases such as type  diabetes. One specific example
metabolomic technologies have progressed the field by is miR-a and miR-b, which are increased in
confirming correlational relationships in large human NAFLD and target IRS and mRNAs encoding en-
cohorts and for the identification of novel metabolites zymes essential for lipid transport and b-oxidation,
with relationships to metabolic diseases. However, the such as CPTa and AMPK a subunit, to simulta-
causality of most of these metabolites for the regu- neously inhibit insulin signaling and lipid-supported
lation of cell functions remains to be elucidated. This ATP synthesis in the liver ().
Regulation of miRNA secretion

It is now clear that miRNAs are secreted by cells and
can be delivered to recipient cells where they func-
tion as endogenous miRNAs. Although miRNAs
are rapidly degraded by ribonucleases in the plasma
(), miRNAs encapsulated by extracellular vesicles
() are highly stable in the circulation ().
Moreover, miRNAs can also travel through the blood
in association with proteins such as argonaute
(Ago), a key element of the RNA-induced silenc-
ing complex that suppresses gene expression, and
within high-density lipoproteins (HDLs) (, ).
The Ago–miRNA complex is secreted by the in-
teraction of vesicle-associated membrane protein 
(VAMP) and synaptosomal-associated protein 
(SNAP) to create a pore allowing export of the
complex (Fig. ).
Although a detailed discussion of the factors reg-
ulating miRNA secretion is beyond the scope of this
review, there is evidence that neutral sphingomyelinase
 (nSMase), an enzyme that catalyzes the synthesis of
ceramides from sphingomyelin, and ceramide accu-
mulation are important for exosome secretion and
miRNA sorting within vesicles (, ). Moreover,
nSMase can inhibit the export of miRNA by HDLs
Figure 5. Potential roles of miRNA in regulating metabolism in peripheral tissues. miRNAs can be (), suggesting an important role for the nSMase–
transported in the circulation and delivered to other tissues to influence metabolic functions. ceramide axis in regulating miRNA secretion. This has
REVIEW
important implications for miRNA “crosstalk” in and insulin action, both in the liver and in distant
NAFLD/NASH, which is characterized by increased tissues. The discovery of new hepatokines and an
nSMase activity and ceramide accumulation (). understanding of their biological functions have
provided new targets for intervention strategies to stop
Liver-derived miRNAs and metabolic regulation the rise of metabolic disease, with FGF analogs
To our knowledge, no study has reported changes being a prominent example.
in miRNA secretion from the liver/hepatocytes However, we are only beginning to appreciate
with NAFLD. However, it is clear that many the sheer magnitude of factors secreted by the liver
miRNAs are increased in the liver with NAFLD, and how these are altered in NAFLD. Rapid de-
that many of these miRNAs are also increased in velopments in mass spectrometry have allowed for a
the circulation, and that these same miRNAs can deeper understanding of cell/tissue secretomes, and
regulate insulin secretion and insulin sensitivity in the depth of information is certain to grow. In this
various cell types (–) (Fig. ). For example, review, we have summarized the metabolic effects of
miR- (), miR- (), and miR- () individual hepatokines, and although this knowledge
impair insulin secretion in pancreatic b-cells, and is beneficial in advancing the understanding of
miR- (, ), miR-a (), miR- (), metabolism, both in health and NAFLD, these dis-
miR-b (), miR- (), and miR- () coveries are tempered by the reality that a diverse
impair insulin sensitivity in the liver, skeletal array of changes link NAFLD to insulin resistance. In
muscle, or adipose tissue. Although these data this context, transomic approaches using tissues
suggest a potentially important role for liver- obtained from well-characterized, clinically relevant
derived miRNAs in regulating glycemic control human cohorts will need to be incorporated using
in NAFLD, definitive evidence for causality is systems biology approaches to interrogate the com-
missing, as these miRNAs are also expressed by, plex control underpinning changes in liver-secreted
and secreted from, other tissues. Approaches products and their relationship with metabolic
aimed at tracking the destination cells of adipose- diseases ().
produced miRNAs have been developed (), A central problem with NAFLD is that it rarely
and the use of this technology would help to clarify manifests specific symptoms and diagnosis is
the capacity for liver-derived miRNAs to regulate frequently incidental. Currently, the only reliable
gene expression and metabolism in distant tissues. means of diagnosing and staging NAFLD is by
miRNAs constitute a minor fraction of all noncoding liver biopsy, which is unsuitable for routine use on
RNAs and other regulatory nucleic acids such as individuals at risk for NAFLD. Hence, noninvasive
P-element–induced wimpy testis (PIWI)-interacting tests are increasingly being used in clinical
RNAs and long noncoding RNA have the capacity to practice to assess NAFLD, leading to concerted
regulate gene expression and to regulate glycaemic efforts to identify new serum biomarkers. Aside
control and lipid homeostasis (–), and they from informing on basic biology, future studies
have been detected in exosomes. Given their rela- that interrogate the hepatocyte or liver secretomes
tively recent discovery, it is not surprising that the using “omics” approaches are well positioned to
relevance of these noncoding RNAs for the physi- identify new biomarkers for the development of
ological and pathophysiological regulation of meta- readily available serum tests able to differentiate
bolism remains to be elucidated. the clinically significant forms of NAFLD and to
monitor disease progression noninvasively.
In closing, the field of “hepatokines” biology is
Conclusion rapidly evolving, and it is our hope that future
work in this domain will help unravel the com-
NAFLD is the most common chronic liver disorder in plexities associated with hepatokine regulation of
developed nations, and the notion that NAFLD is insulin resistance in NAFLD, to delineate pre-
closely linked to the development of insulin resistance viously unappreciated communication between
and type  diabetes is well accepted. Work during the the liver and other organs in metabolic control,
last  years has identified a number of hepatokines and advance the clinical management for the
that play critical roles in regulating lipid metabolism treatment of NAFLD-related comorbidities.
References and Notes

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expression in other tissues [published correction dipeptidyl peptidase-4; ER, endoplasmic reticulum; FGF,
appears in Nature. 2017;545(7653):252]. Nature. fibroblast growth factor; FOXO1, forkhead box O1; GIP,
2017;542(7642):450–455. Acknowledgments gastric inhibitory peptide; GLP, glucagon-like peptide;
378. Henaoui IS, Jacovetti C, Guerra Mollet I, Guay C, Financial Support: M.J.W. is supported by National Health GLUT4, glucose transporter type 4; HDL, high-density li-
Sobel J, Eliasson L, Regazzi R. PIWI-interacting RNAs and Medical Research Council of Australia Senior Research poprotein; HFREP1, hepatocyte-derived fibrinogen-related
as novel regulators of pancreatic beta cell function. Fellowship APP1077703. P.M.M. is supported by a Natural protein 1; HMGB1, high-mobility group box 1 protein; JNK,
Diabetologia. 2017;60(10):1977–1986. Sciences and Engineering Research Council of Canada c-Jun N-terminal kinase; LECT2, leukocyte cell–derived
379. Li P, Ruan X, Yang L, Kiesewetter K, Zhao Y, Luo H, Chen Postdoctoral Fellowship. W.D.N. is supported by a Melbourne chemotaxin 2; LDL, low-density lipoprotein; LECT2, leu-
Y, Gucek M, Zhu J, Cao H. A liver-enriched long non- Research Scholarship (University of Melbourne). M.K.M. is kocyte cell–derived chemotaxin 2; LPC, lysophosphati-
coding RNA, lncLSTR, regulates systemic lipid meta- supported by National Health and Medical Research Council dylcholine; NAFL, nonalcoholic fatty liver; NAFLD,
bolism in mice. Cell Metab. 2015;21(3):455–467. of Australia Career Development Fellowship APP1143224. nonalcoholic fatty liver disease; NASH, nonalcoholic
380. Zhu X, Li H, Wu Y, Zhou J, Yang G, Wang W. lncRNA The authors acknowledge the support of National Health steatohepatitis; NF-kB, nuclear factor kB; nSMase2, neutral
MEG3 promotes hepatic insulin resistance by serving and Medical Research Council of Australia Grants sphingomyelinase 2; PEDF, pigment epithelium–derived
as a competing endogenous RNA of miR-214 to reg- APP1162511 (to M.J.W.) and APP1156508 (to M.J.W.). factor; PPAR, peroxisome proliferator-activated receptor;
ulate ATF4 expression. Int J Mol Med. 2019;43(1): Correspondence and Reprint Requests: Matthew RBP4, retinol binding protein 4; SeP, selenoprotein P; TCA,
345–357. J. Watt, PhD, Department of Physiology, University of tricarboxylic acid; TLR, Toll-like receptor; TSK, Tsukushi.

The Liver as an Endocrine Organ—Linking NAFLD

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The Liver as an Endocrine Organ—Linking NAFLD

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REVIEW

N onalcoholic fatty liver disease (NAFLD) is

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Table 1. Hepatokine Links With NAFLD and Insulin Resistance

Fetuin B Fetub/FETUB ~60 Increased Unknown Promotes insulin resistance in myocytes/hepatocytes

Follistatin Fst/FST 38 Increased Promotes IL-1b production, may promote Unknown

Inhibin bE Inbe 39 Increased Unknown Unknown

SHBG Shbg/SHBG 95 Decreased Suppresses lipogenesis in liver, exacerbates Unknown

Abbreviation: ATGL, adipose triglyceride lipase.

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Metabolite secretion, NAFLD, and oxidative stress (), a well-documented mediator of

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containing phosphatidylethanolamine (). Addi- availability, as shown experimentally by coinfusing

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Regulation of miRNA secretion

References and Notes

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