INTEGRATION OF

METABOLISM
{
DR. FARZANA HAKIM
ASSISTANT PROFESSOR
BIOCHEMISTRY DEPARTMENT
 Major Metabolic Pathways
 1. Glycolysis
 2. Gluconeogenesis
 3. Glycogen Metabolism
 4. Fatty Acid Metabolism
 5. Citric Acid Cycle
 6. Oxidative Phosphorylation
 7. Amino Acid Metabolism
 Only the liver can carry out all of the reaction
the major pathways.
INTEGRATION OF
METABOLISM

Definition:
The co-ordination between three metabolites
(carbohydrate, lipids and proteins) is called

Integration of metabolism
SIGNIFICANCE

Supply of suitable fuel for all tissues, at all time

Under positive caloric balance
A significant proportion of the food energy intake is
stored as either glycogen or fat
Under negative caloric balance
Fatty acids are oxidized in preference to glucose, to
spare glucose for those tissues (Brain and RBC) that
require it under all conditions
INTEGRATION OF
METABOLISM

It should be studied at two levels

• Cellular level

• Tissue level
 The key junction points
 The key junction
points are:-
1 Glucose- 6-
phosphate,
2 Pyruvate and
3 Acetyl CoA.
FEED/FAST CYCLE
Regulation of metabolic
pathway(enzyme changes in fed
state)
 The metabolic pathways are controlled by four different
mechanism
 The availability of substrates (within min.)
 Covalent modification of enzymes(within min.to hours)
 Allosteric regulation(within min.)
 Regulation of enzyme synthesis(within hours to days)
 In fed state ,these regulatory mechanisms ensure that
avaliable nutrients of food (in abundance)are directed
to be stored as glycogen ,triacylglycerol and protein
 A. Allosteric effects
• Allosteric changes usually involve rate-
determining reactions
• Glycolysis in the liver is stimulated following a
meal through phosphofructokinase-1(fructose
2,6bisphosphate)
• Gluconeogenesis is inhibited by Fructose 2,6-
bisphosphate ,an allosteric inhibitor of
fructose 1,6-bisphosphatase
B. Regulation of enzymes by covalent
modification
• Many enzymes are regulated by the
• addition or removal of phosphate
(kinases and phosphatases)
• Cyclic amp mediated PKA and AMPK
• Most of the enzymes regulated are active in the
dephosphorylated form(absoptive state)
• Phosphorylated forms are usually inactive forms
1. Three exceptions are glycogen phosphorylase
kinase
2. Glycogen phosphorylase
3. Hormone -sensitive lipase of
adipose tissue (inactive in dephosphorylated)
C. Induction and repression of enzyme
synthesis
• Increased or decreased enzyme synthesis
• Leads to changes in the total population of active
sites
• In the fed state, elevated insulin levels result in an
increase in the synthesis of key enzymes
• Example is of acetyl coenzyme A carboxylase and
fatty acid synthase
• In fasting glucagon induces expression of PEPCK of
gluconeogenesis
Enzymic changes in fasting
• The metabolic changes observed in fasting
are generally opposite to those in the
absorptive state
• Substrates are not provided by the diet
• They are available from the breakdown of
stores and/or tissues
• Example is lipolysis with release of fatty
acids and glycerol
 ABSORPTIVE (FED)STATE
 The absorptive state is the -4 hours period after ingestion of normal
meal. During this interval, transient increase in plasma glucose,
amino acid and triacyglycerols (main nutrients)occur.
 This results into elevated glucose and amino acids, insulin secretion is
increased from pancreas and glucagon secretions is decreased
 Elevated insulin/glucagon ratio and ready availability of circulating
substrate caused cause increased synthesis of triacyglycerol and
glucagon to be stored (anabolic period)
 During the absorptive period ,all tissues use glucose as a fuel

 During the absorptive period ,metabolic responses of the body is

dominated by alteration of the metabolism of 4 organs i.e. liver
,adipose tissue, muscle and brain
 OVERVIEW OF FASTING
• Multiple reasons of fasting (3-36hrs)
• Plasma levels of glucose, amino acids, and
TAG fall
• Decline in insulin secretion
• Increase in glucagon release
• Fasting is a catabolic period characterized
by degradation of TAG, glycogen, and
protein
There are two priorities:
1. To maintain adequate plasma levels of glucose
to sustain energy metabolism of the brain & red
blood cells
2. To mobilize fatty acids from adipose tissue and
the synthesis and release of ketone bodies from
the liver, to supply energy to all other tissues
 Liver

 Hepatic lipid metabolism:When fatty acids are in

excess, they are exported to the adipose tissue for
storage as TG.

 TG are transported as VLDL particles assembled from

newly synthesized or dietary fatty acids.

 In the fasting state, liver converts fatty acids into ketone

bodies.
The liver is the metabolic hub of the body. It makes the fuel that
supplies the brain, muscles, and other organs.
The liver plays a central role in the regulation of carbohydrate,
lipid, and amino acid metabolism.
The liver removes about two-thirds of the glucose absorbed by the
intestine and converts it to glucose-6-phosphate.

glycolysis glycogen ribose-5-phosphate

The liver also makes glucose by gluconeogenesis and glycogen
Liver
breakdown and releases it into the blood.
 LIVER IN FASTING
• The primary role of liver in energy metabolism
during fasting is maintenance of blood glucose
• It is crucial for synthesis and distribution of fuel
molecules for use by other organs
 A. Carbohydrate metabolism
1. Increased glycogen degradation:
• During the absorptive period, ingested glucose is the
major source of blood glucose
• Several hours later, the increased glucagon to insulin
ratio causes a rapid mobilization of liver glycogen stores
(6hrs)
• ↑Glycogen phosphorylase, ↓Glycogen synthase
• Liver glycogen is nearly exhausted after 10–18 hours of
fasting
2. Increased gluconeogenesis:
• Gluconeogenesis is favored by:
a. Activation of fructose 1,6-bisphosphatase
b. Induction of phosphoenolpyruvate (PEP) carboxy
kinase by glucagon
• It begins 4–6 hours after the last meal
• Becomes fully active as stores of liver glycogen are
depleted
 B. FAT METABOLISM
1. Increased fatty acid oxidation:
• The oxidation of fatty acids is the major source of
energy in hepatic tissue in the fasting state
• Inhibition of PDH by Acetyl CoA causes↑
shunting of pyruvate to OAA
• Phosphorylation (inactivation) of acetyl CoA
carboxylase
• Acetyl CoA activates pyruvate carboxylase which
converts pyruvate to OAA
• By AMP-activated protein kinase (AMPK) removes
the brake on carnitine palmitoyl transferase-1
(CPT-1), allowing β-oxidation to occur
2. Increased synthesis of ketone bodies:
• The liver is unique in being able to
synthesize and release ketone bodies
• Ketogenesis is favored when the
concentration of acetyl CoA, produced
from fatty acid metabolism, exceeds the
oxidative capacity of the TCA cycle
• Ketogenesis starts during the first days of
fasting
• This reduces the need for gluconeogenesis
from amino acid carbon skeletons, thus
preserving essential protein
 The liver removes 2/3 of glucose from the
circulation. This is phosphorylated to G-6-P by
glucokinase and meets different metabolic fates.
Very little is oxidized for supplying energy to the
liver.
 The liver converts excess G-6-P to acetyl CoA for
the synthesis of fatty acids, cholesterol and bile
salts.
Carbohydrate metabolism
 The liver has an active pentose phosphate
in liver
shunt. This supplies NADPH for reductive
biosynthesis.
Amino acid metabolism in
liver
 The liver absorbs most of the dietary
amino acids from the blood.
 Amino acid are preferentially diverted to
protein synthesis rather than catabolism.
 This is possible because the Km for
aminoacyl tRNA synthetase is lower than
that for catabolic enzymes.
 AA catabolism takes place when the
anobolic pathways are saturated.
Amino acid metabolism in
liver
 Liver is the only organ capable of
sequestering N as urea for disposal.

 The α-keto acids derived from aa enter the

gluconeogenesis pathway. They serve as
a primary source of energy for the liver.
ADIPOSE TISSUE IN FASTING

A. Carbohydrate metabolism
• Glucose transport by insulin-
sensitive GLUT-4 into the
adipocyte is depressed due to low
levels of circulating insulin
• This leads to a decrease in fatty
acid and TAG synthesis
 B. Fat metabolism
1. Increased degradation of TAG:
• The activation of hormone sensitive
lipase is enhanced by the elevated
epinephrine and, particularly,
norepinephrine
• These are released from the
sympathetic nerve endings in
adipose tissue
• Glucagon also activates the lipase
2. Increased release of fatty acids:
• Fatty acids are released into the
blood
• Become bound to albumin
• Transported to a variety of tissues
for use as fuel
• The glycerol produced from TAG
degradation is used as a
gluconeogenic precursor by the
liver
3. Decreased uptake of fatty acids:
• In fasting, lipoprotein lipase
activity of adipose tissue is low
• Consequently, circulating TAG of
lipoproteins is not available to
adipose tissue
Urea Cycle
 Metabolic Profiles: Brain
 The brain accounts for 20 % of the energy
requirements of the body, mostly to maintain
membrane potential required for transmission
of nerve impulses.

 Normally, glucose is the sole preferred fuel of

the brain.

 The brain’s consumption of glucose and

oxygen are constant regardless of resting/
sleeping or active/ waking state.
 Metabolic Profiles: Brain
 The brain cannot store glycogen, it must receive
a constant supply of glucose through the blood.

 Brain cells have a glucose transporter, GLUT3,

with a low Km for glucose.

 In the event of starvation or disease, the brain

cells adapt quickly and utilize ketone bodies that
are made in the liver.
Brain in well-fed state
 A. Carbohydrate Metabolism:
 In the well-fed state, the brain uses glucose
exclusively as a fuel, completely oxidizing about
140 g/day glucose to carbon dioxide and water.
The brain contains no stores of glycogen, and
is therefore completely dependent on the
availability of blood glucose. If the blood
glucose levels fall below approximately 30 mg
/dl (normal blood glucose is 70-90 mg/dl)
cerebral function is impaired.
B. Fat Metabolism:
The brain has no significant stores of
triacylglycerols. Blood fatty acids do not efficiently
cross the blood-brain barrier. Thus, the oxidation of
fatty acids is of little importance to the brain
 RESTING SKELETAL MUSCLE IN
FASTING
A. Carbohydrate metabolism
• Low levels of circulating insulin
• Glucose transport into skeletal muscle cells via insulin-
sensitive GLUT-4 is depressed
• Initially use glycogen
• In intense exercise anaerobic glycolysis take place
producing lactate (cori cycle)
 SKELETAL MUSCLE IN FASTING
B. Lipid Metabolism

• After glycogen reserves, free FAs provided by the

mobilization of TAG from adipose tissues
• Contraction based rise in AMP activates AMPK that
phosphorylates and inactivates muscle isozyme of
ACC and allowing FA oxidation
• After 3wks of fast muscle decrease its ketone
bodies utilization(sparing for Brain) and oxidized FA
exclusively
SKELETAL MUSCLE IN FASTING
C. Protein Metabolism
• After few days of fasting rapid breakdown of muscle
protein, releasing amino acids for liver gluconeogenesis
• Muscle donot have Glucagon receptors
• Fall of insulin and rise in Glucocorticoids
• Alanine and glutamine are important glucogenic AA
(BCAA)
 Heart muscle differs from skeletal muscle in
three important ways:
1) The heart is continuously active, wherease skeletal
muscle contracts intermittent on demand
2 ) Heart muscle cells are rich in mitochondria
3 It has a completely aerobic metabolism
4 )The heart contains negligible energy stores such as
glycogen or lipid .

Thus, any interruption of the vascular supply results in

rapid death of myocardial cells .
Heart muscle uses glucose, free fatty acid and ketone
bodies as fuels.
 ■During the first days of fasting, the brain
continues to use only glucose as a fuel.
■ In prolonged fasting (greater than 2-3
weeks) , plasma ketone bodies reach
markedly high levels and are used in
addition to glucose as a fuel by the brain.
■ This decreases the need for
Brain inprotein
fasting
catabolism for
gluconeogenesis.
 Skeletal Muscle Cont.
 The resting muscle prefers fatty acids as fuel.
The active muscle undergoing rapid contraction
prefers glucose.
 During high activity, anaerobic respiration
ensues and glucose metabolism produces high
levels of lactate which is transported to the liver
(Cori cycle).
 During high activity, a large amount of alanine is
formed by transamination of pyruvate. This is
also sent to the liver (alanine) for disposal of N
as urea.
Major metabolic
pathways in brain in
the absorptive state
Brain in fasting

■ During the first days of fasting, the brain continues to

use only glucose as a fuel.
■ In prolonged fasting (greater than 2-3 weeks) ,
plasma ketone bodies reach markedly high levels and
are used in addition to glucose as a fuel by the brain.
■ This decreases the need for protein catabolism for
gluconeogenesis.
B. Fat metabolism
• The brain has negligible stores of
TAG
• The fatty acids bound to albumin do
not efficiently cross the blood-brain
barrier
KIDNEY
 The major task of the kidney is excretion. Water-
soluble metabolic waste products are excreted in
the urine.
 Excess water is removed and the osmolarity
of body fluids is maintained.
 The final composition of urine is determined after
several cycles of filtration and reabsorption to
avoid loss of useful biomolecules.
KIDNEY
 The energy required by the kidneys for this
function is supplied by glucose and fatty acids.

 The kidneys are a minor site of gluconeogenesis

(liver is the major site).

 During starvation, the kidneys can contribute

significant amounts of blood glucose