College of Nursing
Biochemistry
BIOC 102
By
Dr./ Shimaa Nabil Senousy
Biochemistry Lecturer
Biochemistry Division, Chemistry Department, Center of Basic Sciences

College of Nursing
Biochemistry
BIOC 102
ASSESSMENTS Schedule
Assessment I Week 5
Assessment II Week 8
Assessment III Week 12
Final Exam Week 16

College of Nursing
Biochemistry
BIOC 102
Mark Distribution
% Mark
Assessment I 13.3% 20
Assessment II 20% 30
Assessment III 20% 30
Final Exam 46.7% 70
Total 100% 150

Chapter III
Metabolic States of the Body
Feed-Starve Cycle
Intended Learning outcomes
 Identify The Three
Metabolic States.
 Describe The Absorptive and
The Post-absorptive States
of Metabolism.
 Explain Process of Glucose
when the Body is starved of
Fuel.
Lecture 9

Hand Out / Lippincott’s Illustrated Reviews In
Biochemistry
Chapter 24

Chapter
III
Metabolic
States
of
the
Body
Feed-Starve
Cycle
AT = Adipose Tissue
BCAA = Branched Chain Amino Acids
Gluconeogenesis =
Synthesis of Glucose from
Non-Carbohydrate
Sources
IMCL= Intramyocellular Lipids

The Main Metabolic Processes Concerned Include
4. Citric Acid Cycle
1. Carbohydrate Metabolism:
 glucose (Glucolysis)
 glycogenolysis
 gluconeogenesis.
2. Lipid Metabolism:
 Fatty Acid Synthesis
 Lipogenesis
 Lipolysis
 Fatty Acid Oxidation
 Ketogenesis
 Ketolysis
3. Protein Metabolism:
 Protein Synthesis
 Proteolysis
 Amino Acid Oxidation
 Urea Synthesis

The Main Tissues or Organs include
4. Brain
1. Liver 2. Adipose Tissue
3. Muscles

The Feed-Starve Cycle Includes Four Main Stages
1. Food Consumption [Zero Hour].
2. Well –fed State or Absorptive State [4-6 Hours After
Ingestion of Normal Meal].
3. Early Fasting State or Post Absorptive State [18 Hours].
4. Fasting State [36-48 Hours].
5.Starvation State [> 48 Hours of Fasting].

OVERVIEW OF THE ABSORPTIVE STATE
 The absorptive (well-fed) state
is the 2- to 4-hour period after
ingestion of a normal meal.
 the absorptive state is an
anabolic period characterized by
increased synthesis of TAG and
glycogen to replenish fuel stores
and enhanced synthesis of
protein.
 During this absorptive period,
virtually all tissues use glucose
as a fuel.
Glucose
Amino Acid
triacylglycerol
(TAG)
𝑬𝒏𝒉𝒂𝒏𝒄𝒊𝒏𝒈 Pancreating B-Cells to
secrete Insulin
Metabolic alterations in
• liver
• adipose tissue
• skeletal muscle
• brain.
𝑬𝒏𝒉𝒂𝒏𝒄𝒊𝒏𝒈

OVERVIEW OF THE ABSORPTIVE STATE

I. LIVER: NUTRIENT DISTRIBUTION CENTER
venous drainage of
• Gut Nutrients
• Pancreatic Insulin
the hepatic
portal vein
Entry into
general circulation
𝑻𝒉𝒓𝒐𝒖𝒈𝒉 𝑩𝒆𝒇𝒐𝒓𝒆
the liver takes up
• carbohydrates
• Lipids
• amino acids.
Liver acts on nutrients
• metabolized
• stored
• routed to other tissues

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
• The liver is glucose-producing rather than a glucose-using
organ.
• However, after a meal containing carbohydrate, the liver
becomes a net consumer, retaining roughly 60g of every 100g
of glucose presented by the portal system.
• This increased use reflects increased glucose uptake by the
hepatocytes.
• Their insulin-independent glucose transporter (GLUT-2) has
a low affinity (high Km) for glucose and, therefore, takes
up glucose only when blood glucose is high.
• Processes that are upregulated when hepatic glucose is
increased include the following:

A. Carbohydrate metabolism
• Blue text = intermediates of carbohydrate
metabolism
• Brown text = intermediates of lipid
metabolism
• Green text = intermediates of protein
metabolism

High Km Value of an Enzyme
the need for high substrate concentration in
order to achieve maximum reaction
velocity.
𝐦𝐞𝐚𝐧𝐬
• Blue text = intermediates of carbohydrate metabolism
• Brown text = intermediates of lipid metabolism
• Green text = intermediates of protein metabolism
A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER

1. Increased glucose phosphorylation
A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
High Km Value of an Enzyme
the need for high substrate concentration in
order to achieve maximum reaction
velocity.
𝐦𝐞𝐚𝐧𝐬
Elevated Extra-cellular
levels of glucose
Elevated Intra-cellular
Hepatocyte levels of
glucose
insulin-independent
glucose transporter
(GLUT-2) with a high
Km
Glucose glucose 6-phosphate
𝑬𝒏𝒉𝒂𝒏𝒄𝒊𝒏𝒈 𝑽𝒊𝒂
𝑷𝒉𝒐𝒔𝒑𝒉𝒐𝒓𝒚𝒍𝒂𝒕𝒊𝒐𝒏 𝒃𝒚 𝑮𝒍𝒖𝒄𝒐𝒌𝒊𝒏𝒂𝒔𝒆

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
2. Increased glycogenesis
Glucose 6-phosphate glycogen
𝑮𝒍𝒚𝒄𝒐𝒈𝒆𝒏 𝒔𝒚𝒏𝒕𝒉𝒂𝒔𝒆
• Dephosphorylation
• increased availability of glucose 6-phosphate
𝑨𝒄𝒕𝒊𝒗𝒂𝒕𝒆𝒅
𝒃𝒚

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
3. Increased pentose phosphate pathway activity
• Availability of glucose 6-
phosphate.
• active use of nicotinamide
adenine dinucleotide phosphate
(NADPH) in hepatic
Lipogenesis.
pentose phosphate pathway
𝑺𝒕𝒊𝒎𝒖𝒍𝒂𝒕𝒆𝒅
𝒃𝒚

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
4. Increased glycolysis
glycolysis is significant only during the absorptive
period following a carbohydrate-rich meal
Elevated insulin/glucagon ratio
increased amounts of the regulated enzymes of glycolysis:
• glucokinase, PFK-1
• pyruvate kinase , PK
𝑹𝒆𝒔𝒖𝒍𝒕
𝒊𝒏
Glucose Pyruvate [Lactate]
𝑮𝒍𝒚𝒄𝒐𝒍𝒕𝒊𝒄 𝑬𝒏𝒛𝒚𝒎𝒆𝒔
𝑷𝑭𝑲−𝟏/𝑷𝑲

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
4. Increased glycolysis
Glucose Pyruvate [Lactate]
𝑮𝒍𝒚𝒄𝒐𝒍𝒕𝒊𝒄 𝑬𝒏𝒛𝒚𝒎𝒆𝒔
𝑷𝑭𝑲−𝟏/𝑷𝑲
𝑹𝒆𝒔𝒖𝒍𝒕𝒆𝒅
𝒊𝒏
Acetyl CoA
• oxidized for energy in the tricarboxylic acid
(TCA) cycle or
• used as a substrate for fatty acid (FA).
Which either

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
5. Decreased glucose production
low levels of acetyl CoA
(because of using it in FA synthesis)
Pyruvate carboxylase (PC)
Catalyzing
Gluconeogenesis
Inactivated
because of
1ST Mechanism of
Gluconeogenesis Inhibition

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
5. Decreased glucose production
1ST Mechanism of Gluconeogenesis Inhibition

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
5. Decreased glucose production
2ND Mechanism of
Gluconeogenesis Inhibition
High insulin/glucagon ratio
gluconeogenic enzyme
fructose 1,6-bisphosphatase
inactivate

A. Carbohydrate metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
5. Decreased glucose production
Mechanism of Glycogenolysis
Inhibition
dephosphorylation of
• glycogen phosphorylase
• phosphorylase kinase.

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
1. Increased fatty acid synthesis:
Mechanism of de novo synthesis of FA in Liver
FA synthesis, a cytosolic process within
absorptive period

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
1. Increased fatty acid synthesis:
Mechanism of de novo synthesis of FA in Liver
FA synthesis, a cytosolic process within
absorptive period

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
1. Increased fatty acid synthesis:
Mechanism of de novo synthesis of FA in Liver
FA synthesis, a cytosolic process within
absorptive period
Acetyl CoA
Substrate of FA Synthesis
Glucose (Glycolysis) and amino acid
metabolism
pentose phosphate pathway
NADPH
Substrate of FA Synthesis
Acetyl Co-A
Carboxylase
(ACC)
Malonyl CoA
Citrate
AMPK
Adenosine Monophosphate-
Activated Protein Kinase
+
-
(CPT-I)
carnitine palmitoyltransferase-I of
FA oxidation
-
OAA
Oxalo-Acetate
malate
Reduction
pyruvate
Malic Enzyme

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
1. Increased fatty acid synthesis:
Acetyl Co-A Carboxylase (ACC)
Enzyme of FA Synthesis Rate-Determining Step

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
1. Increased fatty acid synthesis:
a. Source of cytosolic acetyl coenzyme A
Aerobic glycolysis
Pyruvate
Decarboxylation
by PDH
Oxaloacetate
(OAA)
Mitochondrial Citrate
Citrate synthase
Of TCA
Cytosolic Citrate
ATP citrate lyase
(induced by insulin)
Acetyl CoA
substrate of ACC plus
OAA
Mitochondria Cytosol

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
1. Increased fatty acid synthesis: a. Source of cytosolic acetyl coenzyme A

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
1. Increased fatty acid synthesis:
b. Additional source of NADPH
OAA
Oxalo-Acetate
Reduction
Citrate leaves the mitochondria (as a result
of the inhibition of isocitrate dehydrogenase
by ATP) and enters the cytosol.
NADPH
Substrate of FA Synthesis
malate
pyruvate
Malic
Enzyme

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
2. Increased triacylglycerol
synthesis TAG:
1. De novo Synthesis of Fatty Acyl
CoA

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
2. Increased triacylglycerol synthesis TGA:
2. Hydrolysis of the TAG Component of Chylomicron remnants removed from the Blood by
Hepatocytes

3. Glycerol 3-phosphate, the backbone for TAG synthesis,
is provided by glycolysis
B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
2. Increased triacylglycerol synthesis TAG:

B. Fat metabolism
I. LIVER: NUTRIENT DISTRIBUTION CENTER
Triacylglycerol TAG Packages
The liver packages these endogenous TAG into very-low-density
lipoprotein (VLDL) particles that are secreted into the blood for use
by extra hepatic tissues, particularly adipose and muscle tissues

I. LIVER: NUTRIENT DISTRIBUTION CENTER
C. Amino acid metabolism
1. Increased amino acid degradation by:
• synthesis of proteins and nitrogen-containing molecules.
• the resulting carbon skeletons being degraded by the liver to pyruvate,
acetyl CoA, or TCA cycle intermediates oxidized for energy or used in FA
synthesis.

I. LIVER: NUTRIENT DISTRIBUTION CENTER
C. Amino acid metabolism
1. Increased amino acid degradation by:
• the resulting carbon skeletons
being degraded by the liver to
pyruvate, acetyl CoA, or TCA
cycle intermediates oxidized for
energy or used in FA synthesis.

I. LIVER: NUTRIENT DISTRIBUTION CENTER
C. Amino acid metabolism
1. Increased amino acid degradation by:
• synthesis of proteins and nitrogen-containing molecules.
• surplus amino acids released into the blood for other tissues to use in protein
synthesis or deaminated.
• the resulting carbon skeletons being degraded by the liver to pyruvate,
acetyl CoA, or TCA cycle intermediates oxidized for energy or used in FA
synthesis.
• The liver has limited capacity to initiate degradation of the branched-chain
amino acids (BCAA) leucine, isoleucine, and valine.
• They pass through the liver essentially unchanged and are metabolized in muscle

I. LIVER: NUTRIENT DISTRIBUTION CENTER
C. Amino acid metabolism
2. Increased protein synthesis:
• The body does not store protein for energy as glycogen or TAG reserves.
• However, a transient increase in the synthesis of hepatic proteins occurs
in the absorptive state, resulting in replacement of any degraded proteins
during fasting.

IV. ADIPOSE TISSUE: ENERGY STORAGE DEPOT

IV. ADIPOSE TISSUE: ENERGY STORAGE DEPOT
A. Carbohydrate metabolism
1. Increased glucose transport:
• Circulating insulin levels are elevated in the
absorptive state, resulting in an influx of
glucose into adipocytes via insulin-sensitive
GLUT-4 recruited to the cell surface from
intracellular vesicles.
• The glucose is phosphorylated by hexokinase.

IV. ADIPOSE TISSUE: ENERGY STORAGE DEPOT
A. Carbohydrate metabolism
2. Increased glycolysis:
• The increased intracellular availability of
glucose results in an enhanced rate of
glycolysis.
• In adipose tissue, glycolysis serves a synthetic
function by supplying glycerol 3-phosphate for
TAG synthesis

IV. ADIPOSE TISSUE: ENERGY STORAGE DEPOT
A. Carbohydrate metabolism
3. Increased pentose phosphate pathway activity:
• Adipose tissue can
metabolize glucose by
means of the pentose
phosphate pathway by
producing NADPH, which
is essential for FA
synthesis.
• De novo synthesis is not a
major source of FA in
adipose tissue

IV. ADIPOSE TISSUE: ENERGY STORAGE DEPOT
B. Fat metabolism
FA added to the TAG stores of adipocytes
provided by:
• Degradation of exogenous (dietary) TAG in
chylomicrons sent out by the intestine.
• Endogenous TAG in VLDL sent out by the liver.

IV. ADIPOSE TISSUE: ENERGY STORAGE DEPOT
B. Fat metabolism
• The FA are released from the
lipoproteins by lipoprotein lipase
(LPL), an extracellular enzyme
attached to the endothelial cells
of capillary walls in many tissues,
particularly adipose and muscle.
• In adipose tissue, LPL is upregulated
by insulin.
• Thus, in the fed state, elevated levels
of glucose and insulin favor storage
of TAG, all the carbons of which are
supplied by glucose.

IV. ADIPOSE TISSUE: ENERGY
STORAGE DEPOT
B. Fat metabolism
In adipose tissue,
• LPL is upregulated by insulin.
• Thus, in the fed state, elevated levels of
glucose and insulin favor storage of TAG.
• Elevated insulin favors the
dephosphorylated (inactive) form of HSL
(Hormone-Sensitive Lipase), thereby
inhibiting lipolysis in the well-fed state.
Elevated
Insulin
Hormone-
Sensitive
Lipase (HSL)
Lipoprotein
Lipase (LPL)
+
-
Release of FA from lipoproteins
storage of TAG
lipolysis
+
+

V. RESTING SKELETAL MUSCLE
• Skeletal muscle uses glucose, amino acids, FA, and ketone bodies
as fuel.
• In the well-fed state, muscle takes up glucose via GLUT-4 (for
energy and glycogen synthesis) and amino acids (for energy and
protein synthesis).
Skeletal muscle, despite its potential for transient
periods of anaerobic glycolysis, is an oxidative
tissue, Why????????
• Skeletal muscle is unique in being able to
respond to substantial changes in the demand
for ATP that accompanies contraction.
• At rest, muscle accounts for ~25% of the
oxygen (O2) consumption of the body, whereas
• During vigorous exercise, it is responsible for
up to 90%.

V. RESTING SKELETAL MUSCLE
A. Carbohydrate metabolism
1. Increased glucose transport:
Increase in Plasma Glucose
Increase Insulin
Increase in glucose transport into muscle cells
(myocytes) by GLUT-4
Glucose is phosphorylated to Glucose 6-
Phosphate by Hexokinase and metabolized to
meet the energy needs of myocytes.

V. RESTING SKELETAL MUSCLE
A. Carbohydrate metabolism
1. Increased glucose transport:
Increase in Plasma Glucose
Increase Insulin
Increase in glucose transport into muscle cells
(myocytes) by GLUT-4
Glucose is phosphorylated to Glucose 6-
Phosphate by Hexokinase and metabolized to
meet the energy needs of myocytes.

V. RESTING SKELETAL MUSCLE
A. Carbohydrate metabolism
2. Increased glycogenesis:
increased insulin
Glycogen Synthesis
Availability of
Glucose 6-Phosphate
+

V. RESTING SKELETAL MUSCLE
B. Fat metabolism
chylomicrons
+
VLDL
Lipoprotein Lipase LPL
Fatty Acids
FA
FA are of secondary importance as a fuel for resting muscle
during the well-fed state, in which glucose is the primary
source of energy.

V. RESTING SKELETAL MUSCLE
C. Amino acid metabolism
1. Increased protein synthesis:
An increase in amino acid
uptake and protein synthesis
occurs in the absorptive
period after ingestion of a
meal containing protein.

V. RESTING SKELETAL MUSCLE
C. Amino acid metabolism
2. Increased branched-chain
amino acid uptake (BCAA):
• Muscle is the principal
site for degradation of
the BCAA because it
contains the required
transaminase.
• The dietary BCAA
escape metabolism by
the liver and are taken
up by muscle, where
they are used for
protein synthesis and as
energy sources.

VI. BRAIN
• The brain accounts for a consistent
20% of the basal O2 consumption of
the body at rest.
• To provide energy, substrates must
be able to cross the blood–brain
barrier [BBB].
• In the fed state, the brain exclusively
uses glucose as a fuel (GLUT-1 of the
BBB is insulin independent).
• Because the brain contains no
significant stores of glycogen, it is
completely dependent on the
availability of blood glucose
• The brain also lacks significant
stores of TAG, and the FA
circulating in the blood.

If blood glucose levels
fall to <50 mg/dl (normal
fasted blood glucose is
70–99 mg/dl), cerebral
function is impaired.
VI. BRAIN
<50 mg/dl

The
intertissue
exchanges
characteristic
of
the
absorptive
period

OVERVIEW OF THE Post-ABSORPTIVE STATE [Fasting]
• post absorptive period of nutrient is a catabolic period
characterized by degradation of TAG, glycogen, and protein.
• Fasting begins if no food is ingested after the absorptive
period.
• It may result from an
1. Inability to obtain food
2. Desire to lose weight rapidly
3. Clinical situations in which an individual cannot eat (trauma,
surgery, cancer, or burns).
Glucose, Amino acids, and TAG
insulin Glucagon

• In fasting, substrates are not provided by the diet
• Substrates are available from the breakdown of stores
and/or tissues, such as glycogenolysis with release of
glucose from the liver, lipolysis with release of FA and
glycerol from TAG in adipose tissue, and proteolysis with
release of amino acids from muscle.
OVERVIEW OF THE Post-ABSORPTIVE STATE [Fasting]
• Recognition that the
changes in fasting are the
reciprocal of those in the
fed state is helpful in
understanding and flow of
metabolism.

Exchange of substrates among the liver, adipose tissue, skeletal
muscle, and brain that is guided by two priorities:
1. the need to maintain adequate glucose to sustain energy in the brain, red
blood cells, and other glucose-requiring tissues.
2. the need to mobilize FA from TAG in white adipose tissue WAT for the
synthesis and release of ketone bodies by the liver to supply energy to other
tissues and spare body protein.
• As a result, blood glucose levels are
maintained within a narrow range in
fasting, while FA and ketone body levels
increase.
• Maintaining glucose requires that the
substrates for gluconeogenesis (such
as pyruvate, alanine, and glycerol) be
available.
OVERVIEW OF THE Post-ABSORPTIVE STATE [Fasting]

VIII. LIVER IN FASTING
Hepatic metabolism is distinguished from peripheral (or
extrahepatic) metabolism, WHY??????????
The primary role of the liver in
fasting is
1. maintenance of blood glucose
through the production of
glucose (from glycogenolysis and
gluconeogenesis) for glucose-
requiring tissues.
2. synthesis and distribution of
ketone bodies for use by other
tissues.

VIII. LIVER IN FASTING

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
1. Increased glycogenolysis:
• Liver glycogen is exhausted by 24 hours of
fasting, hepatic glycogenolysis is a
transient response to early fasting.
• Glycogen degradation as part of the
overall metabolic response of the liver
during fasting.

Glucose
VIII. LIVER IN FASTING
A. Carbohydrate metabolism
1. Increased glycogenolysis:
Glucagon
Glycogen Phosphorylase Kinase
Glycogen Phosphorylase
cAMP-Dependent Protein Kinase A
+
+
+
+
• The increased glucagon causes a rapid
mobilization of liver glycogen stores.
• Protein Kinase A (PKA-mediated
phosphorylation and activation) of
glycogen phosphorylase kinase that
phosphorylates (and activates)
glycogen phosphorylase.

Increased
Glycogen
Degradation
Glycogenolysis
1 2
Phosphorylation of
glycogen synthase
(Activation) simultaneously
inhibits glycogenesis.

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Increased gluconeogenesis:
The carbon skeletons for gluconeogenesis are
derived primarily from:
1. glucogenic amino acids and lactate from
muscle
2. glycerol from adipose tissue.

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Increased gluconeogenesis:
The carbon skeletons for gluconeogenesis are
derived primarily from:
1. glucogenic amino acids and lactate from
muscle
2. glycerol from adipose tissue.

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Increased gluconeogenesis:
Enzymes Activating gluconeogenesis :
1. fructose 1,6-bisphosphatase

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Increased gluconeogenesis:
Enzymes Activating gluconeogenesis :
2. Pyruvate Carboxylase

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Increased gluconeogenesis:
Enzymes Activating gluconeogenesis :
3. Lactate Dehydrogenase

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Increased gluconeogenesis:
Enzymes Activating gluconeogenesis :
4. Glucose-6-Phosphatase

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Increased gluconeogenesis:
Enzymes Activating gluconeogenesis :
5. Phosphoenol Pyruvate CarboxyKinase PEPCK

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Inhibition of glycolysis:
Enzymes Involved :
1. Inactive Phosphofructo-Kinase-1 Inhibits Glycolysis

VIII. LIVER IN FASTING
A. Carbohydrate metabolism
2. Inhibition of glycolysis:
Enzymes
Involved :
Glucagon
Hormone
+
Protein
Kinase A
-
Pyruvate
Kinase

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
• The major pathway for
catabolism of fatty acids is a
mitochondrial pathway called β -
oxidation, in which two-carbon
fragments are successively re
moved from the carboxyl end of the
fatty acyl CoA, producing acetyl
CoA, NADH, and flavin adenine
dinucleotide (FADH2).
• The oxidation of FA (β -oxidation)
obtained from TAG hydrolysis in
adipose tissue is the major source
of energy in hepatic tissue in the
fasted state.

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
• The major pathway for
catabolism of fatty acids is a
mitochondrial pathway called β -
oxidation, in which two-carbon
fragments are successively re
moved from the carboxyl end of the
fatty acyl CoA, producing acetyl
CoA, NADH, and flavin adenine
dinucleotide (FADH2).
• The oxidation of FA (β -oxidation)
obtained from TAG hydrolysis in
adipose tissue is the major source
of energy in hepatic tissue in the
fasted state.

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
Glucagon Hormone
+
Adenosine Monophosphate Activated Protein Kinase A
(AMPK)
Acetyl Co-Carboxylase (ACC)
-
Malonyl Co-A ↓
Active Carnitine Palmitoyl
Transferase-I (CPT-I)
Transfer Acyl gp
β -oxidation ↑
Results in
Acetyl Co-A ↑

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
Glucagon Hormone
+
Adenosine Monophosphate Activated
Protein Kinase A (AMPK)
Acetyl Co-Carboxylase (ACC)
-
Malonyl Co-A ↓
Active Carnitine Palmitoyl
Transferase-I (CPT-I)
Transfer Acyl gp
β -oxidation ↑
Results in
Acetyl Co-A ↑

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
Glucagon Hormone
+
Adenosine Monophosphate Activated
Protein Kinase A (AMPK)
Acetyl Co-Carboxylase (ACC)
-
Malonyl Co-A ↓
Active Carnitine Palmitoyl
Transferase-I (CPT-I)
Transfer Acyl gp
β -oxidation ↑
Results in
Acetyl Co-A ↑

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
Glucagon Hormone
+
Adenosine Monophosphate Activated
Protein Kinase A (AMPK)
Acetyl Co-Carboxylase (ACC)
-
Malonyl Co-A ↓
Active Carnitine
Palmitoyl
Transferase-I (CPT-I)
Transfer Acyl gp
β -oxidation ↑
Results in
Acetyl Co-A ↑

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
1. The NADH (from β-oxidation) inhibits
the TCA cycle and shifts OAA to malate.
2. This results in acetyl CoA being
available for ketogenesis.
3. NADH inhibits TCA CYCLE enzymes
resulting in availability of acetyl CoA for
Ketone body synthesis.
NADH inhibits TCA CYCLE
enzymes resulting in
availability of acetyl CoA
for Ketone body synthesis.

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
1. The NADH (from β-oxidation) inhibits
the TCA cycle and shifts OAA to malate.
2. This results in acetyl CoA being
available for ketogenesis.
3. NADH inhibits TCA CYCLE enzymes
resulting in availability of acetyl CoA for
Ketone body synthesis.
NADH inhibits TCA
CYCLE enzymes
resulting in
availability of acetyl
CoA for Ketone body
synthesis.

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
1. The NADH (from β-oxidation) inhibits
the TCA cycle and shifts OAA to malate.
2. This results in acetyl CoA being
available for ketogenesis.
3. NADH inhibits TCA CYCLE enzymes
resulting in availability of acetyl CoA for
Ketone body synthesis.
NADH inhibits TCA CYCLE enzymes resulting
in availability of acetyl CoA for Ketone body
synthesis.
1. α –Ketoglutarate dehydrogenase
2. Isocitrate dehydrogenase

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
1. The NADH (from β-oxidation) inhibits
the TCA cycle and shifts OAA to malate.
2. This results in acetyl CoA being
available for ketogenesis.
3. NADH inhibits TCA CYCLE enzymes
resulting in availability of acetyl CoA for
Ketone body synthesis.
NADH inhibits TCA CYCLE enzymes resulting
in availability of acetyl CoA for Ketone body
synthesis.
1. α –Ketoglutarate dehydrogenase
2. Isocitrate dehydrogenase

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
The acetyl CoA is also activates PC and inhibits
PDH, thereby favoring use of pyruvate in
gluconeogenesis.

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
The Acetyl CoA is also activates PC and inhibits
PDH, thereby favoring use of pyruvate in
gluconeogenesis.

VIII. LIVER IN FASTING
B. Fat metabolism
1. Increased fatty acid oxidation:
The Acetyl CoA is also activates PC and inhibits
PDH, thereby favoring use of pyruvate in
gluconeogenesis.

VIII. LIVER IN FASTING
B. Fat metabolism
2. Increased ketogenesis (Ketone Bodies Synthesis):
• Ketogenesis, which starts during the first days of fasting, is favored
when the concentration of acetyl CoA from FA oxidation exceeds the
oxidative capacity of the TCA cycle.
• Ketogenesis releases CoA, insuring its availability for continued FA
oxidation.
• The availability of circulating water-soluble ketone bodies is
important in fasting because they can be used for fuel by most
tissues, including the brain, once their blood level is high enough.
• Ketone body concentration in blood increases from ~50 µM to ~6mM
in fasting. This reduces the need for gluconeogenesis from amino
acid carbon skeletons, thus preserving essential protein.
• Ketone bodies are organic acids and, when present at high
concentrations, can cause ketoacidosis.

VIII. LIVER IN FASTING
B. Fat metabolism
2. Increased ketogenesis (Ketone Bodies Synthesis):
The liver is unique in being able to synthesize and release ketone bodies for use
as fuel by peripheral tissues but not by the liver itself because liver lacks
thiophorase

VIII. LIVER IN FASTING
B. Fat metabolism
2. Increased ketogenesis (Ketone Bodies
Synthesis):
1. The NADH (from β-oxidation) inhibits the TCA
cycle making acetyl CoA available for
ketogenesis.
2. The NADH (from β-oxidation) favors synthesis of
3-hydroxybutyrate (Ketone Bodies)
The generation of free
CoA during ketogenesis
allows fatty acid oxidation
to continue.

IX. ADIPOSE TISSUE IN FASTING
A. Carbohydrate metabolism
Glucose transport by insulin-sensitive
GLUT-4 into the adipocyte and its
subsequent metabolism are
decreased because of low levels of
circulating insulin. This results in
decreased TAG synthesis.
Insulin Levels ↓
Glucose transport by insulin-
sensitive GLUT-4 into the
adipocyte ↓
TAG synthesis ↓

IX. ADIPOSE TISSUE IN FASTING
B. Fat metabolism
1. Increased fat degradation:
Hydrolysis of stored fat (TAG)
+
Insulin ↓ + Epinephrine ↑
Active Protein kinase A
Active Hormone-Sensitive Lipase (HSL)
+
+
1. fatty acid release (FA).
+

IX. ADIPOSE TISSUE IN FASTING
B. Fat metabolism
1. Increased fat degradation:
Hydrolysis of stored fat (TAG)
+
Insulin ↓ + Epinephrine ↑
Active Protein kinase A
Active Hormone-Sensitive Lipase (HSL)
+
+
2. Glycerol
+
Note: Glycerol cannot be metabolized by
adipocytes because they lack glycerol kinase .

IX. ADIPOSE TISSUE IN FASTING
B. Fat metabolism
Glycerol
𝐆𝐥𝐲𝐜𝐞𝐫𝐨𝐥 𝐊𝐢𝐧𝐚𝐬𝐞
𝐈𝐧 𝐋𝐢𝐯𝐞𝐫
Glycerol 3-phosphate
gluconeogenic precursor
1. Increased fat degradation:

IX. ADIPOSE TISSUE IN FASTING
B. Fat metabolism
2. Glycerol
Glycerol 3-phosphate
gluconeogenic precursor
1. Increased fat degradation:
TAG↑
in the liver
Dihydroxyacetone
phosphate (DHAP)
glycolysis or gluconeogenesis
Glycerol Kinase
In Liver
reversal of the
DHAP reaction
plasma FA concentration ↓

IX. ADIPOSE TISSUE IN FASTING
B. Fat metabolism
2. Increased fatty acid release:
Hydrolysis of stored fat (TAG)
fatty acid release (FA) into the blood
+
FA-Bound to Albumin
transported to a variety of
tissues for use as fuel.
Ex: Liver
+
Oxidation
Acetyl Co-A
TCA Cycle

IX. ADIPOSE TISSUE IN FASTING
B. Fat metabolism
3. Decreased fatty acid uptake:
Less active
lipoprotein lipase (LPL)
In Adipose
During Fasting
Lipoprotein
FA ↓
 FA in circulating TAG of lipoproteins are
less available to adipose tissue than to
muscle.

X. RESTING SKELETAL MUSCLE IN FASTING
switches from glucose
to FA as its major fuel
source in fasting.
1. Resting muscle
2. Exercising muscle
 It uses its glycogen stores as a
source of energy.
 During intense exercise,
glucose 6-phosphate derived
from glycogen is converted to
lactate by anaerobic glycolysis
glycogen glucose 6-phosphate Lactate
Anaerobic glycolysis
Gluconeogenesis in Liver

X. RESTING SKELETAL MUSCLE IN FASTING
2. Exercising muscle
 It uses its glycogen stores as a
source of energy.
 During intense exercise, glucose
6-phosphate derived from
glycogen is converted to lactate
by anaerobic glycolysis.
 As these glycogen reserves are
depleted, free FA provided by the
degradation of TAG in adipose
tissue become the dominant
energy source.
 The contraction-based rise in
AMP activates AMPK that
phosphorylates and inactivates
the muscle isozyme of ACC,
decreasing malonyl CoA and
allowing FA oxidation.

Adenosine Monophosphate Activated
Protein Kinase A (AMPK)
Acetyl Co-Carboxylase (ACC)
-
Malonyl Co-A ↓
β -oxidation ↑
Results in
Acetyl Co-A ↑
X. RESTING SKELETAL MUSCLE IN FASTING
2. Exercising muscle
The contraction-based rise in AMP activates
AMPK that phosphorylates and inactivates
the muscle isozyme of ACC, decreasing
malonyl CoA and allowing FA oxidation.

X. RESTING SKELETAL MUSCLE IN FASTING
A. Carbohydrate Metabolism
 Glucose transport into skeletal myocytes via insulin-sensitive GLUT-4.
 Subsequent glucose metabolism are decreased because circulating insulin levels
are low.
 Therefore, the glucose from hepatic gluconeogenesis is unavailable to muscle and
adipose.
Glucose
transport via insulin-
sensitive GLUT-4 into
Skeletal Myocytes
glucose Metabolism ↓
Circulating Insulin Levels ↓

X. RESTING SKELETAL MUSCLE IN FASTING
B. Lipid Metabolism
During the first 2 weeks of fasting
Adipose Tissue
FA ketone Bodies
Liver
After about 3 weeks of fasting
Muscle uses FA from adipose tissue and
ketone bodies from the liver as fuels.
 Muscle using of ketone bodies ↓
(sparing them for Brain).
 Alternatively, oxidizes FA.
FA Oxidation
Acetyl CoA
+
PDH kinase
-
PDH
spares pyruvate, which is
transaminated to Alanine and
used by liver for
gluconeogenesis.

X. RESTING SKELETAL MUSCLE IN FASTING
C. Protein Metabolism
During the first few days of fasting In the second week of fasting
Proteolysis of
Muscle Protein ↑
Rabid
Degradation
Amino Acids
Ex: Alanine and Glutamine mainly from
Catabolism of Branched Chain Amino
Acids (BCAA)
Gluconeogenesis
In Liver
Insulin ↓
(No Glucagon Receptors in Muscles)
Instead, Brain uses ketone bodies as a source of energy.
Rate of Muscle Proteolysis ↓
The need for Glucose as a fuel for the brain ↓

XI. BRAIN IN FASTING
During the early days of fasting
the brain continues to use only glucose as a
fuel.
Glucogenic Precursors,
such as
1. amino acids from proteolysis.
2. glycerol from lipolysis.
Hepatic Gluconeogenesis
Blood Glucose

XI. BRAIN IN FASTING
In prolonged fasting (be yond 2–3 weeks )
 Plasma ketone bodies reach significantly
elevated levels and replace glucose as the
primary fuel for the brain.
 This reduces the need for protein
catabolism for gluconeogenesis: Ketone
bodies spare glucose and, thus, muscle
protein.
As the duration of a fast extends from
overnight to days to weeks, blood glucose
levels initially drop and then are maintained
at the lower level (65–70 mg/dl).]
Note:

XI. BRAIN IN FASTING
As the duration of a fast extends from overnight
to days to weeks,
 blood glucose levels initially drop and
 then are maintained at the lower level (65–
70 mg/dl).]

OVERVIEW OF
THE Post-
ABSORPTIVE
STATE [Fasting]
The metabolic changes
that occur during
fasting insure that all
tissues have an
adequate supply of fuel
molecules.

XII. KIDNEY IN LONG-TERM FASTING
As fasting continues into early starvation and beyond,
in late fasting,
Renal Cortex
expresses Gluconeogenesis Enzymes
Ex: glucose 6-phosphatase
 50% of gluconeogenesis occurs here.
 A portion of this glucose is used by the kidney itself.
The kidney also provides compensation for the acidosis that accompanies the increased
production of ketone bodies (organic acids).
Glutamine
released from the muscle’s metabolism of BCAA
Renal Glutaminase and
Glutamate Dehydrogenase
α-Ketoglutarate
Substrate for
Gluconeogenesis
𝑵𝑯𝟑
𝑵𝑯𝟑 + 𝑯+ → 𝑵𝑯𝟒
+
Urine
decreasing the acid
load in the body

XII. KIDNEY IN LONG-TERM FASTING
in late fasting,  50% of gluconeogenesis occurs here.
 A portion of this glucose is used by the kidney itself.
The kidney also provides compensation for the acidosis that accompanies the increased
production of ketone bodies (organic acids).
Glutamine
released from the muscle’s metabolism of BCAA
Renal Glutaminase and
Glutamate Dehydrogenase
α-Ketoglutarate
Substrate for
Gluconeogenesis
𝑵𝑯𝟑
𝑵𝑯𝟑 + 𝑯+ → 𝑵𝑯𝟒
+
Urine
decreasing the acid
load in the body
 In long-term fasting, there is a switch
from nitrogen disposal in the form of
urea to disposal in the form of NH4
+.
 As ketone body concentration rises,
enterocytes, typically consumers of
glutamine, become consumers of
ketone bodies. This allows more
glutamine to be available to the
kidney.

OVERVIEW
OF
THE
Post-ABSORPTIVE
STATE
[Fasting]

XIII. CHAPTER SUMMARY
The flow of intermediates through metabolic pathways is controlled by four
regulatory mechanisms:
1) the availability of substrates,
2) Allosteric activation and inhibition of enzymes,
3) covalent modification of enzymes,
4) induction-repression of enzyme synthesis.

XIII. CHAPTER SUMMARY
 In the absorptive state, the 2- to 4-hour period after ingestion of a meal, these
mechanisms insure that available nutrients are captured as glycogen,
triacylglycerol (TAG), and protein.
 During this interval, transient increases in plasma glucose, amino acids, and TAG
occur, the last primarily as components of chylomicrons synthesized by the
intestinal mucosal cells.
 The pancreas responds to the elevated levels of glucose with an increased
secretion of insulin and a decreased secretion of glucagon.
 The elevated insulin/glucagon ratio and the ready availability of circulating
substrates make the absorptive state an anabolic period during which virtually all
tissues use glucose as a fuel.
 In addition, the liver replenishes its glycogen stores, replaces any needed hepatic
proteins, and increases TAG synthesis.
 The TAG are packaged in very-low-density lipoproteins, which are exported to
the peripheral tissues.
 Adipose tissue increases TAG synthesis and storage, whereas muscle increases
protein synthesis to replace protein degraded since the previous meal.
 In the fed state, the brain uses glucose exclusively as a fuel.

 In fasting, plasma levels of glucose, amino acids, and TAG fall, triggering a decline in
insulin secretion and an increase in glucagon and epinephrine secretion.
 The decreased insulin/counter regulatory hormone ratio and the decreased availability of
circulating substrates make the fasting state a catabolic period.
 This sets into motion an exchange of substrates among the liver, adipose tissue, skeletal
muscle, and brain that is guided by two priorities:
1) the need to maintain adequate plasma levels of glucose to sustain energy metabolism of the
brain and other glucose-requiring tissues and
2) the need to mobilize fatty acids (FA) from adipose tissue and release ketone bodies from
liver to supply energy to other tissues.
 To accomplish these goals, the liver degrades glycogen and initiates gluconeogenesis,
using increased FA oxidation to supply the energy and reducing equivalents needed
for gluconeogenesis and the acetyl coenzyme A building blocks for ketogenesis.
 The adipose tissue degrades stored TAG, thus providing FA and glycerol to the liver.
 The muscle can also use FA as fuel as well as ketone bodies supplied by the liver.
 The liver uses the glycerol for gluconeogenesis.
 Muscle protein is degraded to supply amino acids for the liver to use in gluconeogenesis but
decreases as ketone bodies increase.
 The brain can use both glucose and ketone bodies as fuels.
 From late fasting into starvation, the kidneys play important roles by synthesizing glucose
and excreting the protons from ketone body dissociation as ammonium(NH4+).
XIII. CHAPTER SUMMARY

XIII.
CHAPTER
SUMMARY

XIII. CHAPTER SUMMARY

XIII. CHAPTER SUMMARY

XIII. CHAPTER SUMMARY

XIII. CHAPTER SUMMARY

XIII. CHAPTER SUMMARY

XIII. CHAPTER SUMMARY

XIII. CHAPTER SUMMARY

XIII. CHAPTER SUMMARY