METABOLIC

INTERRELATIONSHIPS

SADIAH ACHMAD

DEPARTMENT OF BIOCHEMISTRY
FACULTY OF MEDICINE
UNISBA
1
 OVERVIEW

METABOLISM :
 Interconversion of chemical compounds in the body
 Their pathways
 Their interrelationships
 The mechanism that regulate the flow of metabolites
through the pathway

2
METABOLIC PATHWAYS :
 Anabolic : synthesis of larger & complex compounds
from smaller precursor
 Catabolic : breakdown of larger molecules , involving
oxidative reaction, producing reducing equivalents,
ATP.
 Amphibolic : “cross roads” of metabolism, links
between anabolic & catabolic
Normal metabolism : includes adaptive to periods of
starvation, exercise, pregnancy & lactation
Abnormal metabolism : result from nutritional deficiency,
enzym deficiency, abnormal secretion of hormones,
action of drugs/toxins

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• All metabolic pathways do not operate in every tissue at
any given time, depend on : nutritional & hormonal
status. Need to know qualitatively which pathways are
functional & how they relate to one another.

• Metabolic processes : glycolysis, glycogenesis,

glycogenolysis, gluconeogenesis, TCA cycle, lipogenesis,
FA oxidation, ketogenesis, AA oxidation, protein
synthesis, proteolysis, urea synthesis.

4
Important to know :

• Which tissues are most active in these

various processes.

• When these processes are most active.

• How these processes are controlled &

coordinated in different metabolic states.

5
 COMPARTMENTATION OF METABOLIC
PATHWAYS AT SUBCELLULAR LEVEL

• Cytosol : glycolysis, glycogenesis, glycogenolysis, P-P

pathway, lipogenesis
• Mitochondria : TCA, β-oxidation FA, respiratory chain,
ATP synthesis
• Endoplasmic reticulum (membrane) : TAG synthesis,
drug metabolism

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Metabolic pathways are regulated by :
Rapid mechanism : modify activity of existing enzyme
- allosteric
- covalent modification (response to H)
Slow mechanism : synthesis of enzyme

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 PRODUCTS OF DIGESTION

Products of digestion provide tissues with :

• Building block → biosynthesis of complex molecule
• Fuel → to power living process
Water soluble products are transported directly to the liver
via portal vein → to the tissues
Products of lipid digestion, secreted as chylomicrons into
the lymphatics, entering circulation via thoracic duct →
to the tissues
All products of digestion (CH, lipid, protein) →
AcetylCoA → TCA → ATP
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Fig 16-1. Outline of the pathways for the catabolism of dietary carbohydrate, protein, and fat. All the
pathways lead to the production of acetyl-CoA, which is oxidized in the citric acid cycle, ultimately
yielding ATP by the process of oxidative phosphorylation.
Fig 13-2 Role of the respiratory chain of mitochondria in the conversion of food energy to ATP.
Oxidation of the major foodstuffs leads to the generation of reducing equivalents (2H) that are
collected by the respiratory chain for oxidation and coupled generation of ATP.
 PATHWAYS THAT PROCESS THE MAJOR
PRODUCTS OF DIGESTION.

GLUCOSA
• Glycolysis → triose-P → pyruvate → Acetyl CoA → TCA
lactate
• Glycogenesis → glycogen
• Pentose –P pathway → NADPH, ribose
• Gluconeogenesis : lactate, glycerol, AA → glucose
• Triose-P → glycerol → TAG
• Pyruvate & intermediate of TCA → synthesis AA
• Acetyl CoA → FA, cholesterol (→ steroids), KB

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 Fig 16-2. Overview of
carbohydrate metabolism
showing the major
pathways and end products.
Gluconeogenesis is not
shown.
 FATTY ACID
• LCFA → β- oxidation → Acetyl CoA → TCA
cholesterol → steroids
ketone bodies, FA
esterification → TAG

AMINO ACID (ess, noness)

• Protein synthesis
• Transamination → deamination → NH3 → urea
carbon skeleton → TCA
gluconeogenesis
KB
• Several AA : precursor of other compounds : purin, pyrimidin, Hs,
NTs

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To understand the interrelationships of the pathways →
to learn the changes in metabolism during :
the starve-feed cycle.
• Feed refers to the intake of meals (variable fuel input)
after which the fuel is stored (as glycogen & TAG) to
meet metabolic needs of fasting.
• ATP cycle functions within this cycle. Cells of the
body need continuous supply of energy for ATP
synthesis

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Humans are able to use a variable fuel input to
meet a variable metabolic demand

Variable fuel input

storage fuels
O2
ADP + Pi Variable
metab
demand
ATP

CO 2 + H 2 O + urea

15
• In the fed state : enough supply of CH.
Metabolic fuel for most tissues is glucose.
• In fasting state, glucose must be spared for use by
CNS & RBCs.
Therefore : - muscle & liver oxidize fatty acids
- liver synthesizes ketone bodies from
fatty acids & export to the muscle &
other tissue → to form energy (ATP)

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• As glycogen reserve become depleted , amino
acids from protein turnover & glycerol from
TAG are used for gluconeogenesis.

• The formation & utilization of reserve TAG &

glycogen, and the extent to which the tissues
take up & oxidize glucose are controlled by
insulin & glucagon

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Disposition of glucose, amino acids, and fat
by various tissues in the well-fed state

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WELL-FED STATE : diet supplies energy requirements
• Glucose passes from intestinal epithelial cells via
portal vein to the liver
• AAs are partially metabolized in the gut before released
into portal blood → to the liver
• Chylomicron (TAG) → lymphatics → thoracic duct →
subclavian vein → to the rest of the body

GLUCOSE
In the liver glucose is converted into :
 glycogen : glycogenesis
 pyruvat & lactate : glycolysis
 ribose-P & generation of NADPH : P-P pathway
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* Glucose passes through the liver to the other organs :
Brain, RBCs, adrenal medulla, adipose tissues, muscle.
* In adipose tissues : glucose → glycerol moiety → TAG
* In muscle : glucose → glycogen
→ glycolysis → TCA → ATP
* Lactate & pyruvate from glycolysis in other tissues →
liver → oxidized → CO2
→ TAG

In the well-fed state, the liver uses glucose, does

not engage in gluconeogenesis → Cori cycle is
interrupted
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AMINO ACID
Liver removed some AAs from portal blood, most of them
pass through to be distributed to other organs. This is
especially important for essential AAs which are needed
for all cells for protein synthesis.
In the liver : → protein synthesis
→ excess AAs → oxidized completely to
CO2, H2O, urea
→ intermediates → lipogenesis
→ TAG

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 CHYLOMICRON (TAG)
• Lipoprotein lipase (LPL) hydrolyzes most of TAG in
chylomicron → FFA → taken up by adipocytes →
reesterified with glycerol-3P (derived from glucose) →
TAG → stored : fat droplets.
• Chylomicron remnants → to the liver
TAG are hydrolyzed by lysosomal lipase → FFA →
reesterified with glycerol-3P (from free glycerol &
glucose) → TAG
• This TAG (from diet fat) plus TAG produced by the novo
synthesis from glucose & AAs are packed into VLDL →
secreted into blood

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VLDL
• LPL hydrolyzes TAG in VLDL → FFA → taken up by
adipocytes → reesterified → TAG → stored in adipose
tissues
• Most of TAG of human adipose tissue originates from
the diet rather than from de novo synthesis.

β-cells of pancreas are very responsive to the influx of

glucose & AAs in the fed state .
• Glucose enters β cells → oxidized → ATP ↑ → closes
ATP-sensitive K channels → depolarizes the cell →
intracellular Ca ↑ → insulin release.
• β-cells release insulin during & after eating → essential
for metabolism of nutrients by liver, muscle, adp tissue. 23
EARLY FASTING STATE
• In early fasting state, hepatic glycogenolysis
maintains blood glucose.
• Lactate, pyruvate, alanine from periphere are
diverted from oxidation & FA synthesis into
glucose formation → completing Cori cycle.
• Glucagon inhibits glycogen synthase &
activates glycogen phosphorylase in the liver
→ glycogenolysis → glucose is released into
the blood for use by the brain & RBCs

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• Muscle glycogen can not contribute directly to
plasma glucose (lack glucose-6Pase) → glucose-
6P is used for energy yielding metabolism in the
muscle itself.
• Acetyl CoA from FA oxidation in muscle inhibits
pyruvate dehydrogenase → pyruvate accumulate.
Most of pyruvate is transaminated to ala → taken
up by the liver → transaminated → pyruvate →
gluconeogenesis

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FASTING STATE

• In fasting state, concentration of glucose in portal

blood falls → insulin secretion ↓ , glucagon
secretion ↑ → skeletal muscle & adipose tissue
take up less glucose

• Hepatic gluconeogenesis is mandatory

• Cori cycle & alanine cycle play important roles

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FASTING STATE
• Adipose tissue :
Ratio insulin/glucagon ↓ → inhibit lipogenesis,
inactivates LPL, activates HS lipase →
lipolysis : TAG →
*glycerol → to the liver → gluconeogenesis
*FFA → liver, heart & skeletal muscle →
metab fuel (sparing glucose)
• Liver : greater capacity for FA β-oxidation →
acetyl CoA ↑ → KB → used as fuels for
skeletal muscle, heart muscle & brain
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FASTING STATE
• As fasting more prolonged → ↑ AAs released from
protein catabolism → to the liver & kidney :
gluconeogenesis
• AAs especially from skeletal muscle, supply most of
carbon for glucose synthesis
• Protein in the muscle are hydrolyzed → AAs:
Most are metabolized
Released :- largest amount : ala & gln
- the other: metabolized to intermediates
(pyruvate & α-KG) → ala & gln

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FASTING STATE
• Branched-chain AAs : major source of N to produce
ala & gln in muscle
BC AA : transamination → BC α-keto acid, partially
released into blood to the liver : →
 glucose (valine)
 KB (leucine)
 glucose & KB (isoleucine)
• Part of gln released from muscle is used by intestinal
epithel, lymphocytes & macrophages

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FASTING STATE
• Gln is important fuel for enterocytes &
lymphocytes, which require it for synthesis of
pyrimidines & purines.
• Gln is converted to glu → transaminated with
pyruvate to form α-KG & alanine.
• α – KG is converted to malate in TCA →
converted to pyruvate by malic enz.
• Pyruvate is needed for alanine formation in
enterocytes
This pathway in enterocytes : glutaminolysis
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FASTING STATE
• In lymphocytes & macrophages, ASP is the major end
product of glutaminolysis
• ASP is used for energy needs & for nucleotide
synthesis
Synthesis of glucose in the liver is closely linked to
synthesis of urea
Most AAs are transaminated with α-KG → glu & α-keto
acids (used for glucose synthesis)
Glu provides 2 forms of N for urea synthesis :
- ammonia (oxid deamination by glu dehydrogenase)
- ASP (transamination of OA by asp aminotransferase)
Source of ammonia & citrulline : gut mucosa
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FASTING STATE
• FA oxidation in liver :
 provides most of ATP needed for gluconeogenesis
 acetyl CoA :- very little is oxidized completely
- mostly is converted to KB → source
of energy for many tissues
• KB suppress proteolysis & BCAA oxidation in muscle
& ↓ alanine release → -↓ muscle wasting
-↓ glucose synthesis in liver

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FASTING STATE
• As long as high KB levels are maintained →
 less need for glucose
 less need for glucogenic AAs
 less need for breaking down muscle tissue
• This because insulin level remain high enough
to suppress partially muscle proteolysis, as long
as glucose level remain high enough to
stimulate insulin release

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FASTING STATE
• Hepatic gluconeogenesis :
 muscle & gut supply substrate (ala)
Adipose tissue supplies ATP (FA oxid)
• This cooperation among major tissues is dependent on
the appropriate blood hormone levels
• Fasting : glucose levels are lower : →
 reducing insulin secretion
 increasing release of glucagon & epinephrine
 reducing formation of thyroid H → reduces daily
basal energy requirement by up to 25%
• This response is useful for survival

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EARLY REFED STATE

• TAG is metabolized as in the well fed state

• Liver extract glucose poorly
• Glycogen is formed by indirect pathway :
The liver remains in gluconeogenic for a few hours,
however this pathway provides glucose-6P for
glycogenesis rather than providing blood glucose
Glucose is catabolized in peripheral tissue to lactate
& is converted in the liver to glycogen by
gluconeogenesis
AA from gut → gluconeogenesis → liver glycogen

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EARLY REFED STATE

Glycogen

direct indirect
Glucose glucose 6- P lactate / AA

• After rate of glucose synthesis declines, liver glycogen

is sustained by direct synthesis from blood glucose

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 INTERRELATIONSHIP OF TISSUES IN
NUTRITIONAL AND HORMONAL STATES

PREGNANCY
• Fetus : require nutrient
• It uses glucose, AAs, lactate, FA & KB for
energy & synthesis
• Lactate produced in placenta is partly directed
to the fetus & the rest enters maternal
circulation → to the liver (Cory cycle)
• During pregnancy, the starve-feed cycle is
disoriented
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Metabolic Changes in Normal Pregnant Woman

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• Placenta secretes placental lactogen, estrogen &
progesterone :
Placental lactogen stimulates lipolysis in adipose
tissue
Estrogen & progesterone induce insulin resistance
• After meals, pregnant woman enter the starved state
more rapidly, because of ↑ consumption of glucose &
AAs by the fetus → maternal hypoglycemia
Plasma glucose, AAs & insulin levels fall rapidly
Glucagon & placental lactogen level rise →
stimulates lipolysis & ketogenesis

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LACTATION
• In late pregnancy, placental lactogen & maternal
prolactin induce LPL in mammary gland , providing
development of milk-secreting cells & ducts
• During lactation the breast uses glucose for lactose
& TAG synthesis and for major energy source
• AAs are taken up for protein synthesis
• Chylomicron & VLDL provide FA for TAG
synthesis
If these compouds are not supplied by the diet → must
be supplied by proteolysis, gluconeogenesis &
lipolysis → eventually resulting in maternal
malnutrition & poor quality milk

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 OBESITY at
• Results from overeating → accumulation of
massive amount of body fat
• Body fat originates primarily from diet, small
amount are synthesized in the liver, transported
to adipose tissue or synthesized in adipocytes
• Large amount of food consumed → too long in
well-fed state & fasting phase is too short to use
stored fat
• For unknown reason, neural control of calorie
intake to balance energy expenditure is
abnormal
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• Obese mouse (oblob, discovered in 1950): defective
gene (ob gene, cloned in 1994) which encode a protein :
OB protein or leptin (slimming effect)
Leptin is produced in adipocyte & detectable in blood
The defect : nonsense mutation → produce no leptin
Injection of leptin → ↑ energy expenditure & reduce
eating → marked weight loss
Leptin also reduces appetite & weight of normal mouse
• Obese human, generally do not have defective obgene,
in fact they tend to have high blood level of leptin →
suggest that their nervous system is insensitive to leptin

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 OBESITY

• Most common type : number of adipocytes does not

increase but large (hypertrophy), engorge with TAG
If obesity developed before puberty : ↑ in number of
adipocytes → hyperplasia & hypertrophy
• Obese in man tend to be centered on abdomen &
mesenteric fat. In woman on hips
• Risk factor in development of variety of diseases
• Syndrome X (metabolic syndrome) :
 obese
 hypertension
 dyslipidemia
 insulin resistance (→ DM2)
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• Obesity → insulin resistance : impair insulin receptor
function :
 Number or affinity of insulin receptor ↓
 Normal insulin binding, but abnormal post-receptor
responses
• Quantity of body fat is proportional to the degree of insulin
resistance
• Insulin resistance is induced by :
 TNF α & resistin (oppose the action of insulin)
 ↓ secretion of adiponectin
→ plasma insulin levels are greatly ↑ in obese → DM
type 2

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 DIABETES MELLITUS

DIABETES MELLITUS TYPE 1

• Characterized by : - hyperglycemia
- hypertriglyceridemia
- episodes of ketoacidosis
• Defect of β-cells → absence of insulin → derangement
of metabolism of CH, lipid & protein
• Insulin /glucagon ratio decrease → liver is always
gluconeogenic & ketogenic → hyperglycemia
• In muscle & adipose tissue : GLUT – 4 remains
sequestered within cells → inability to take up glucose
→ hyperglycemia
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• Uncontrolled proteolysis in skeletal muscle providing
fuel for gluconeogenesis → maintain hyperglycemia
• Uncontrolled lipolysis in adipose tissue → ↑ plasma FA
→↑ FA oxidation in the liver → ↑ KB production →
ketoacidosis
• Excess FA taken by the liver → synthesized TAG →
VLDL synthesis ↑
Low activity of LPL → VLDL & chylomicron can not
be cleared from blood → hypertrigliceridemia
• Every tissue plays catabolic role → severe wasting of
body tissues
• Unless insulin is administered → death

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METABOLIC CHANGES IN TYPE-1 DM ( IDDM )

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METABOLIC CHANGES IN DM TYPE 1

CH metabolic changes → hyperglycemia

• ↓ glucose uptake into the cells
• ↓ glycolysis
• ↑ glycogenolysis in the liver
• ↓ glycogenesis
• ↑ gluconeogenesis
• ↓ TCC

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1.Carbohydrate metabolic changes  hyperglycemia
a). Decrease glucose uptake into the cells of muscle & adipose
tissue, caused by low activity of glucose transporter (GLUT4)

Glucose
Insulin
Insulin receptor Glucose transporter

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b). Decrease glycolysis, caused by low
activity of glycolytic key enzymes :
- Hexokinase / glucokinase
- Phosphofructokinase
- Pyruvate kinase

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Glucose
Glucokinase /
hexokinase

Glucose-6 P
+
Fructose-6 P
Phospho fructo +
kinase Insulin

Fructose-1,6 bi P

2 Triose-P
+

2-Phosphoenol pyruvate ( PEP )

Pyruvate kinase
2-Pyruvate
c). Increase glycogenolysis in the liver, caused
by high activity of phosphorylase in the liver

d). Decrease glycogenesis, caused by

low activity of glycogen synthase

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Glycogen
-
Phosphorylase

Glucose-1 P Insulin

Glucose-6 P

Glucose-6 P-ase
-
Glucose

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 Glucagon Insulin

+ +

Adenylate Phospho di-

cyclase esterase
ATP cAMP 5 AMP

Glycogenolysis

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 Glucose

Glucose-6 P

Glucose-1 P
UTP
Insulin
Uridine diphosphate
glucose ( UDPG )
+
Glycogen
Primer Glycogen
synthase

Glycogen

61
e). Increase gluconeogenesis caused by high
activity of gluconeogenic key enzymes :
- Glucose-6 phosphatase
- Fructose-1,6 biphosphatase
- PEP carboxykinase
- Pyruvate carboxylase

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 Glycogen

Glucose
Hexokinase Glucose-6
glucokinase phosphatase
+ Glucose-6 P
Insulin
Fructose-6 P
+ Phospho Fructose-1,6
fructokinase biphosphatase
Fructose-1,6 bi P

Insulin Insulin

PEP car-
PEP
Pyruvate
+
boxykinase kinase

Oxalo acetate Pyruvate

Pyruvate
Pyruvate
carboxylase
Oxalo acetate

Malate Malate TCC

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Mitochondrial matrix
f). Decrease TCC activity, caused by decrease
of citrate synthase activity, or lack of
oxaloacetate.

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 Glucose
Lipids
Protein

Pyruvate FFA Amino acids

Insulin
+
Citrate Acetyl Co A
synthase

Oxalo acetate citrate

Malate T.C.C Iso citrate

Fumarate
 Keto glutarate
Succinate

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2. Lipid metabolic changes → ketoacidosis,
hypertriglyceridemia & hypercholesterolemia
* Energy production failure from glucose  ↑ lipolysis
in adipose tissues  ↑ plasma free FA  ↑  oxidation 
↑ acetyl CoA production

Insulin

Hormon sensitive lipase

* Triglycerides Free fatty acid

Glycerols
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 FFA
 oxidation
Acetyl CoA
TCC
 Hydroxy  Methyl Glutaryl CoA
( HMG CoA )
HMG CoA
reductase HMG CoA lyase

Cholesterol Keton bodies

(Hypercholesterolemia) (Keto acidosis)

Extra-hepatic tissues

Acetyl CoA

TCC 67
 FFA (Blood)
Liver

VLDL
Intestine

VLDL (TG) Chylomicron (TG)

Extra hepatic tissues

+
Insulin Lipoprotein lipase

Glycerol FFA
Decrease of LPL activity
→hypertriglyceridemia 68
3. Protein metabolic changes
Glucogenic AAs from diet & from proteolysis in
the skeletal muscle enter gluconeogenesis
pathway in the liver to maintain blood glucose
concentration → hyperglycemia

69
DIABETES MELLITUS TYPE 2
Characterized by :
• Obese
• Hyperglycemia
• Hypertriglyceridemia
• Ketoacidosis rarely develop
Some patients develop transient episodes of
ketoacidosis

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DM type 2

CH metabolic changes :
• Insulin resistance
• Insufficient production of insulin to overcome
the resistance → impaired β-cells function →
relative insulin deficiency → hyperglycemia
• Impair insulin receptor function →
translocation of GLUT 4 is decreased →
hyperglycemia

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Lipid metabolic changes

• Increased VLDL synthesis is the result of ↑

hepatic TAG synthesis which is stimulated by
hyperglycemia & hyperinsulinemia
• LPL is inactive → TAG in VLDL &
chylomicron is not hydrolyzed →
hypertriglyceridemia
• Ketoacidosis is rarely developed, because
enough insulin to prevent uncontrolled release
of FFA from adipose tissue & taken up by the
liver
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METABOLIC CHANGES IN TYPE-2 DM ( NIDDM )

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 Glucagon Insulin
epinephrine etc

+ +

Adenylate cyclase Phosphodiesterase

ATP cAMP 5 AMP

Lipolysis

74
LIVER DISEASE
• Advanced liver disease → metabolic derangement
especially for AAs
• In cirrhosis, liver can not convert ammonia into urea &
gln → blood ammonia ↑
• Ammonia arises from :
action of glutaminase, glu dehydrogenase, adenosine
deaminase
during metabolism in intestine & liver
from intestinal lumen ( bacteria split urea into
ammonia & CO2)
• Ammonia is toxic to CNS → leads to coma
( sometimes occur in patients with liver failure)
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 LIVER DISEASE
• In advanced liver disease, plasma aromatic AAs
> BCAAs (defective hepatic catab)
• Aromatic AAs & BCAAs are transported into
the brain by the same carrier system
• Elevated ratio of aromatic AAs to BCAAs → ↑
brain uptake of aromatic AAs (trp) → ↑
synthesis of NTs (serotonin) → neurological
abnormalities of liver disease

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LIVER DISEASE
• Liver is a major source of IGF-1
• Patient with cirrhosis deficient IGF-1
synthesis in response to GH → muscle
wasting
• Sometimes demonstrate insulin resistance →
DM 2
• Patients sometimes die of hypoglycemia
because liver is unable to maintain blood
glucose level by gluconeogenesis

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 RENAL DISEASE

• In CRF : - levels of AAs normally metabolized by

kidney (glu, gly, pro & citr) ↑
- N end products (urea, uric acid,
creatinin) accumulate → need dialysis
• This is worsened by high protein intake or
accelerated ptoteolysis
• Intestinal bacteria can split urea into ammonia &
Liver uses ammonia & α-keto acids to form
nonessential AAs
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 RENAL DISEASE

• Diet therapy : high CH & limited AAs as much

as possible to essential AAs → liver synthesizes
nonessential AAs from TCC intermediates.
This diet may delay the need for dialysis

• Detriment in dialysis patients : carnitine

deficiency, resulting from reduced intake
(meat) & reduced renal function → may lead to
cardiac & skeletal myopathy due to reduced
ability to oxidize FA
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81
REFERENCE

1. Devlin, TM. : Textbook of Biochemistry with Clinical

Correlations. 6th edition., 2006, A Wiley Medical
Publication.
2. Harper, H.A. : Illustrated Biochemistry. 27th edition,
2006, A Lange Medical Book

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