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Synthesis of Triacylglycerols
Glycolipid Metabolism
Cholesterol Metabolism
Blood Lipoproteins
Digestive Lipid Metabolism
Emulsification of Dietary lipids in the small intestines
lipase activity
- detergent property of bile salt and
peristalsis
> Pancreatic activity
Excess
Cholesterol
Bile
Cholesterol Catabolism into Bile Salts
Cholesterol Cholate
OH
COO -
HO
HO
Cholesterol OH
7-hydroxylase
Bile Salts
Breakdown products of cholesterol
Amphipathic molecules
Bile Salt
Phospholipid
Functions of Micelles
Transport cholesterol from the liver into the
intestine via the biliary tree
Sinusoidal Membrane
ABCG5/G8
Cholesterol
ABCB4
Phospholipid
Bile salts 24
Phospholipids 11
Cholesterol 2
Biliary Lipid Transport
Liver
Duodenum
Biliary
Transport
and
Storage Jejunum
Ileum
Colon
Fat Digestion
Liver
Duodenum
Biliary
Transport
and
Storage Jejunum
Ileum
Colon
Fat Digestion
I
II IIII
I II
Dietary Triglycerides Phospholipids
Cholesterol
Duodenum
Biliary
Transport
and
Storage Jejunum
Ileum
Colon
Cholesterol Absorption
Intestinal
Lymph Enterocyte Lumen
Cholesterol
ACAT
Cholesteryl
Ester
Triglyceride Absorption
2 Fatty Acid
+
Monoglyceride
DGAT
Triglyceride
Phospholipid Absorption
Intestinal
Lymph Enterocyte Lumen
Fatty Acid
+
Lysophospholipid
Phospholipid
Chylomicron Formation
Intestinal
Lymph Enterocyte Lumen
Phospholipid
Triglyceride
With
apoB48 Cholesteryl
Ester
Figure 23.1 Absorption and transport of dietary fat.
1. Extramitochondrial cytosol
2. Microsomal smooth endoplasmic reticulum
3. Mitochondrial mitochondrion
Glucose
Glycolysis (cytosol)
Pyruvic acid
Pyruvate DH (mitochondria)
Acetyl CoA
Extramitochondrial Lipogenesis
How did acetyl CoA get into the cytosol?
Acetyl CoA + Oxaloacetate
Citrate Mitochondrion
*****************************************
Citrate Cytosol
citrate lyase
Acetyl CoA + Oxaloacetate
Figure 23.13 Transport of acetyl units from the mitochondrion to the cytoplasm. The inner
mitochondrial membrane has carriers for citrate, pyruvate, and malate but not for acetyl-CoA
and oxaloacetate.
Downloaded from: StudentConsult (on 6 May 2011 11:33 PM)
2005 Elsevier
Pathway for the movement of acetyl-CoA units from within the
mitochondrion to the cytoplasm for use in lipid and cholesterol
biosynthesis. Note that the cytoplasmic malic enzyme catalyzed reaction
generates NADPH which can be used for reductive biosynthetic reactions
such as those of fatty acid and cholesterol synthesis.
Extramitochondrial Lipogenesis
Rx 1 CH3COSCoA Acetyl CoA
Enz-biotin-*COO- + ADP + Pi
CH3CO-CH2-COS-ACP Acetoacetyl-ACP
NADPH + H+ ketoacyl reductase
NADP
CH3 CHOH-CH2-COS-ACP
B-hydroxyacyl-ACP
Extramitochondrial Lipogenesis
Rx 5. Dehydration
CH3CHOH-CH2-COS-ACP B-hydroxyacyl-
ACP
H2O hydratase
Rx 6. Reduction
CH3-CH=CH-COS-ACP&,B-unsaturated acyl-ACP
NADPH + H+
Enoyl reductase
NADP
CH3-CH2-CH2-COS-ACP Butyryl-ACP
(Acyl-ACP)
Extramitochondrial Lipogenesis
Sources of NADPH
1. HMP shunt
2. Malic enzyme rxn
Citrate oxaloacetate
Malate
NADP Malic enzyme (NADP malate DH)
NADPH CO2
Pyruvate
Extramitochondrial Lipogenesis
Rx 6. Another round of rxn going back to rx 3
CH3-CH2-CH2-COS-ACP Butyryl-ACP
CH3-CH2-CH2-CH2-CH2-COS-ACP Acyl-ACP
primer first second
acetyl CoA malonyl malonyl
Extramitochondrial Lipogenesis
CH3-(CH2)14-COS-ACP Palmitoyl-ACP
deacylase (thioesterase)
CH3-(CH2)14-COOH Palmitic acid
Summary of Extramitochondrial Lipogenesis
Takes place in the cytosol
Conversion of acetyl CoA to malonyl CoA is the rate-limiting step or
committed step
Acetyl CoA carboxylase is the rate-limiting or committed enzyme
Biotin is the prosthetic group of acetyl CoA carboxylase
Acetyl CoA carboxylase is inhibited by palmitic acid (negative
feedback mechanism)
Avidin, a protein found in raw egg white, inhibits the committed step
by binding and removing biotin from the reaction
Regulation of Lipogenesis
A. Regulation of acetyl CoA carboxylase activity
1. Inhibited by palmitic acid and other long-chain fatty
acyl CoA negative feedback inhibition
2. Activated by citrate, an indicator of a plentiful supply of
acetyl CoA, converts the enzyme from the inactive dimer
to an active polymeric form
3. Hormonal regulation
a) Insulin activates the enzyme by promoting its
dephosphorylation
b) Glucagon and epinephrine inactivates the
enzyme by promoting its phosphorylation
via cAMP-dependent protein kinase
Regulation of lipogenesis
2. Avidin, a protein found in raw egg white, inhibits the
committed step by binding biotin, the prosthetic group of
acetyl CoA carboxylase
3. Nutritional state that favors lipogenesis
a) Well-fed state high carbohydrate diet
b) High intake of sucrose fructose bypasses the
phosphofructokinase control point in glycolysis
4. Nutritional state that depresses lipogenesis
a) restricted caloric intake
b) high fat diet
c) deficiency of insulin, e.g. diabetes mellitus
Regulation of lipogenesis
5. Induction and repression of enzyme synthesis
a) Insulin stimulates transcription of the gene that codes
for acetyl CoA carboxylase and fatty acid synthase complex
b) Glucagon antagonizes this effect
c) High fat diet containing PUFA inhibits expression of key
enzymes of glycolysis and lipogenesis
6. Other mode of regulation by long-chain fatty acyl CoA
a) It inhibits the mitochondrial tricarboxylate (citrate)
transporter
b) It also inhibits pyruvate dehydrogenase
De Novo Synthesis of Fatty Acids
Carboxylation of acetyl
CoA to malonyl CoA Carboxylation of AcetylCoA to
Regulators of acetylCoA malonylCoA by AcetylCoA
carboxylase carboxylase
Activators: insulin,Inc. Rate limiting step in fatty acid
CHO intake, fat-free diet synthesis
Inhibitors: malonyl CoA, Coenzyme: Biotin
palmitoyl
CoA,epinephrine,
fasting, high fat diet
Figure 23.14 Regulation of acetyl-CoA carboxylase by allosteric effectors and hormones.
Green arrow, stimulation; red arrow, inhibition. AMP, adenosine monophosphate; cAMP, cyclic AMP.
Downloaded from: StudentConsult (on 6 May 2011 11:33 PM)
2005 Elsevier
De Novo Synthesis of Fatty Acids
Fatty acid synthase: a
multienzyme complex
Substrate: AcetylCoA and Carbons 15 and 16 of palmitic acid from
MalonylCoA priming acetyl CoA
End Product: Palmitic acid Carbons 1-14 of palmitic acid are
Site: Cytosol derived from 7 malonyl CoA ( 2 carbons
Priming Molecule: Acetyl CoA from malonyl CoA are added 7 times to
Rate-limiting enzyme: Acetyl the priming acetylCoA molecule
CoA carboxylase NADPH + H+ are from HMP-Shunt
Primary enzyme of synthesis:
Fatty acid synthase
hepatosplenomegaly,
mental retardation in
Gaucher's disease Glucocerebrosidase Glucocerebroside
infantile form, long bone
degeneration
Globotriaosylceramide; also
kidney failure, skin
Fabry's disease -Galactosidase A called ceramide trihexoside
rashes
(CTH)
Niemann-Pick
disease, more info
all types lead to mental
below Sphingomyelinase Sphingomyelin
retardation,
Types A and B see info below LDL-derived cholesterol
hepatosplenomegaly,
Type C1 see info below LDL-derived cholesterol
early fatality potential
Type C2
Type D
Disorder Enzyme Deficiency Accumulating Substance Symptoms
Krabbe's disease;
mental retardation,
globoid Galactocerebrosidase Galactocerebroside
myelin deficiency
leukodystrophy
same symptoms as Tay-
Sandhoff-Jatzkewitz Hexosaminidase A and
Globoside, GM2 ganglioside Sachs,progresses more
disease B
rapidly
mental retardation,
GM1 ganglioside: b -
GM1 gangliosidosis GM1 ganglioside skeletal abnormalities,
galactosidase
hepatomegaly
Sulfatide lipodosis; mental retardation,
metachromatic Arylsulfatase A Sulfatide metachromasia of
leukodystrophy nerves
cerebral degeneration,
Fucosidosis -L-Fucosidase Pentahexosylfucoglycolipid thickened skin, muscle
spasticity
Farber's hepatosplenomegaly,
Acid ceramidase Ceramide
lipogranulomatosis painful swollen joints
Metabolism of the Eicosanoids
Prostaglandins (PGs)
thromboxanes (TXs)
leukotrienes (LTs)
Prostanoid Synthesis via the Cyclooxygenase
Pathway
Prostanoids are synthesized by prostaglandin H synthase (PGHS)
PGHS has two separate enzyme activities:
1. cyclooxygenase 2. peroxidase
PGHS has two isoenzymes:
1. PGHS 1 2. PGHS 2
- each having cyclooxygenase and peroxidase activities
Most prostanoids are synthesized from arachidonic acid
Arachidonic acid is released from membrane phospholipid by
phospholipase A2
Cyclooxygenase: A Suicide Enzyme
Major
Eicosanoid site(s) of Major biological activities
synthesis