Metabolic Interrelationships

Sylvia Rianissa Putri

 Sources of Metabolic Fuel
• Three major sources of metabolic fuel
in our diets: Carbohydrate, Lipid and Protein

• Liver cells can perform all of synthesis and

degradation

• Most other cell are primarily limited to

– catabolize glucose and fatty acids to generate ATP
through mitochondrial oxidative phosphorylation .
 Five energy conversion processes:
1. Carbohydrate metabolism
(glycolysis & gluconeogenesis)

2. Lipid metabolism (fatty acid

oxidation & synthesis)

3. Amino acid metabolism

(oxidation and synthesis)

4. Citrate cycle

5. Oxidative phosphorylation.
 Each Organ Has a Unique Metabolic Profile
• Metabolic patterns of brain, muscle, adipose tissue,
kidney, and liver are very different.

• Brain:
- use glucose as fuel in a well-fed person
- use ketone bodies (acetoacetate &
3 hydroxybutyrate) during starvation.

• Adipose tissue:
- is specialized for synthesis, storage, &
mobilization of triacylglycerols.
 Each Organ Has a Unique Metabolic Profile

• Kidney produces urine and reabsorbs glucose, takes up

glutamine and metabolizes it to ammonia which
maintains acid-base homeostasis (complementary),
converts citrulline to arginine, takes up phenylalanine
and glycine, releases tyrosine and serine.
• Liver:
– can rapidly mobilize glycogen and carry out
gluconeogenesis to meet glucose needs of other
organs
– plays a central role in regulation of lipid metabolism.
Liver functions:
1. determine what dietary nutrients & metabolic fuels
are distributed to peripheral
2. as a glucose regulator that helps:
– remove excess glucose from blood when carbohydrate
levels are high
– produce glucose from glycogen & gluconeogenesis,
when serum glucose levels are low.
– regulate serum glucose
• through insulin & glucagon signaling pathways

modulate metabolic flux through glycolysis,

gluconeogenesis, and glycogen metabolism.
Glucose 6-Phosphate
• is retained by liver
• most is used to synthesize
liver glycogen.
• is dephosphorylated in
liver & released into blood
and used by other tissues,
in particular brain.
• is converted to
1. 6-phosphoglucolactone, if liver need NADPH for
biosynthetic reactions,
2. fructose-6-phosphate & then metabolized by glycolytic
pathway and pyruvate dehydrogenase reaction to yield
acetyl-CoA for use in lipid biosynthesis, oxidative
phosphorylation or ketogenesis.
MUSCLE:
• Two types of muscle that play a major role in
metabolic integration:
1. skeletal muscle:
– Amount of FA, glucose or ketone bodies for metabolic fuel
is different, it depend on physical movements required
(rapid burst of activity or endurance activity)
– primarily uses FA released from adipose tissue as a source
of energy.
– FA are oxidized to generate acetyl-CoA, then used by
citrate cycle to produce NADH and FADH2 for oxidative
phosphorylation.

2. cardiac muscle uses mostly FA and ketone bodies as

metabolic fuel
MUSCLE:
• When muscle contraction in very short burst of activity,
(serving a tennis ball about 2-3 seconds), muscles use of
intracellular ATP pool.

• If muscle activity is about 3-8 seconds, ATP pool is replenished

with ATP from by phosphocreatine

• Creatine kinase catalyzes reversible resynthesis of

phosphocreatine when cellular ATP level return to normal
MUSCLE:
• When muscle contraction continues beyond about an
hour, glycogen storage becomes depleted.

• As glucose levels decline, ATP production for muscle

contraction depend on
– fatty acids from adipose tissue
– ketone bodies produced in liver

• During long term starvation, skeletal muscle provide

amino acid as substrates for liver and kidney
gluconeogenesis.
ADIPOSE TISSUE

• stores and releases fatty acids from adipocytes (fat

cells) in response to metabolic needs.

• secretes peptide hormones called adipokines

(adipocyte hormones) that is used in metabolic
integration .
Triacylglycerol cycle
1. Systemic component:
• recycles FA from adipose tissue by hormone-sensitive
lipase and TG synthesis in liver cells
2. Intracellular component:
• recycles FA that enter adipocytes following TG
hydrolysis by lipoprotein lipase and TG synthesis in
adipocytes.

• Under normal conditions:

~75% FFA released by
hormone-sensitive lipase
in adipocytes is returned to
TG through either systemic
or intracellular routes.
BRAIN

• In normal condition,
– brain requires + 120 g glucose a day to produce ATP
– to maintain brain function, glucose requirement must be
met by liver.

• During prolonged starvation,

- brain adapts to using ketone bodies (acetoacetate
and D-β-hydroxybutyrate)

• Fatty acids cannot cross blood-brain barrier because

they are bound to carrier proteins
 Primary metabolic pathways
in six organs
1. Liver:
• is control center of metabolic network
• regulate metabolite flux between tissues & organs
• export glucose & TG to peripheral tissues.

2. Brain requires a constant input of glucose

3. Cardiac muscle use of FA and ketone bodies & glucose at a

low level.

4. Adipocyte tissue: exchange of FA & TG between liver and

adipocyte tissue
 Primary metabolic pathways
in six organs
5. Skeletal muscle:
• uses glucose and FA from liver and dietary for ATP
synthesis
• exports lactate back to liver to complete Cori Cycle
during times of prolonged physical activity.
• Glutamine and alanine transport excess nitrogen
product of protein degradation in muscle to liver
and kidney for excretion

6. Kidney: excrete nitrogen (form of urea) from AA

degradation in liver
Primary metabolic pathways in major organs
Insulin and glucagon are most important global metabolic
regulators in humans
 Food Intake and Starvation Induce Metabolic
Changes

• Insulin signals fed state:

– Insulin stimulates synthesis of glycogen and TG
& proteins.

– Increased secretion of insulin and decreased

secretion of glucagon.

– glycogen is synthesized in muscle and liver.

 Food Intake and Starvation Induce Metabolic
Changes
• Glucagon signals a low blood-glucose level:
– Glucagon stimulates glycogen breakdown and
gluconeogenesis by liver & TG hydrolysis by adipose
tissue.

– degradation of glycogen and by gluconeogenic

pathway form glucose.

– hydrolysis of TG release fatty acids.

– Liver & muscle use FA, whereas glucose is conserved

for use by brain.
Metabolic adaptations to starvation

• Primary metabolic provide enough glucose for brain to

maintain normal neuronal cell functions.

• Brain cannot use fatty acids (cannot cross blood-brain

barrier).

• Red blood cells are also dependent on serum glucose.

• Mature erythrocytes lack mitochondria is not able to

utilize FA
 Metabolic adaptations to starvation
• At onset of starvation (24 hour
fast):
1. Degradation of liver glycogen
resulting in a drop in serum
glucose
2. Increase gluconeogenic in
liver and kidneys to generate
glucose for brain and
erythrocytes.
Major substrates:
- glycerol from TG
- alanine from
transamination reaction
- lactate from anaerobic
glycolisis
 Metabolic adaptations to starvation
• At onset of starvation (24 hour
fast):
3. In muscle cells. Glutamate is
deaminated to generate α-
ketoglutarate that used for
gluconeogenesis

4. Adipose tissue use FA from TG

hydrolysis (glucose is
available for brain and
erythrocytes).

FA used as metabolic fuel

during starvation are derived
from TG hydrolisis
 Metabolite flux between major tissues and organs in human
body under starvation
• First 24 hours:
- glycogen stores are
depleted
- adipose tissue release FA
from TG and transported to
skeletal muscle and heart.
- In liver, acetyl-CoA is used
production of ketone
bodies as energy source for
heart and brain
 Metabolite flux between major tissues and organs in human
body under starvation

• First 24 hours:
- AA from protein
degradation in skeletal
muscle provides C for
gluconeogenesis in liver
& kidney.

• Glucose from
gluconeogenesis is used by
brain and erythrocytes
Four major alterations in metabolic flux in order to
survive long periods of time without food:
1) Increased TG hydrolysis in adipose tissue.
2) Increased gluconeogenesis in liver and kidney cells.
3) Increased ketogenesis in liver cells.
– high rates of FA oxidation, & decreased of oxaloacetate
for gluconeogenesis

– acetyl-CoA in liver increase dramatically

– High ketogenesis produces acetoacetate and D-β-

hydroxybutyrate for export to other tissues.

– brain and heart can use ketone bodies

– erythrocytes are totally dependent on glucose because
they lack mitochondria
4) Protein degradation in skeletal muscle tissue.
Sources of blood glucose in fed,
fasting, and starved states.

From Ruderman NB, et al.

In: Hanson RW, Mehlman MA, eds.
Gluconeogenesis: Its Regulation in
Mammalian Species. 1976:518.
© 1976 John Wiley & Sons
Fuel Choice During Exercise Is Determined by Intensity
and Duration of Activity

• 100-meter sprint use stored ATP, creatine

phosphate, and anaerobic glycolysis to
produce energy.

• In marathon, energy from oxidation of both

muscle glycogen and FA derived from adipose
tissue (a highly aerobic process).
 Ethanol Alters Energy Metabolism in Liver

Ethanol consumption leads to an accumulation of NADH

1. Inhibits gluconeogenesis 2. inhibits fatty acid oxidation

by preventing oxidation of
lactate to pyruvate. Excess NADH lead to FA
synthesis.
lactate will be accumulated
TG accumulate in liver (fatty
hypoglycemia & lactic acidosis liver)
DM tipe 1
• Lack of insulin  decrease uptake and
utilization of glucose  increased
gluconeogenesis and lipolysis  ketogenesis.
• Prolong uncontrolled diabetes  ketoacidosis
+ hyperosmolar hyperglycemic  coma.
 DM tipe 2

ubiquitinasi

SOCS-1
SOCS-3

Jalur transduksi sinyal insulin dalam meregulasi

glikogen sintase (Nelson and Cox, 2008).
• Sitokin lain:
– Resistin.
– IL-1β.
– IL-6.
– TNFα.
– SOCS-6.
Beberapa gen yang diregulasi oleh insulin (Nelson and Cox, 2008).
• Kelaparan sel  katabolisme KH, lipid,
protein, dan glukoneogenesis.
• Hiperglikemia dan hiperinsulinemia  sintesis
TAG di hepar  VLDL darah meningkat 
lipogenesis