Substrates for lipid synthesis
Phosphatidate is a precursor of storage and membrane lipids
Formed by the addition of two fatty acids to glycerol 3-phosphate
Triacylglycerol synthesis
Triacylglycerol (TAG) synthesis is completed by TAG synthase
complex bound to the endoplasmic reticulum
The liver is the primary site of triacylglycerol synthesis
Liver TAGs are transported to muscle for use as fuel
or to adipose tissue for storage
Phospholipid synthesis
Phosphatidate is also a precursor for phospholipids
Phospholipid synthesis combines diacylglyceride with an
alcohol, one of the components must be activated
Ethanolamine
Choline
Inositol
Synthesis from an activated diacylglycerol
This reaction is driven by hydrolysis of PPi
The activated phosphatidyl unit then reacts with the hydroxyl
group of an alcohol
Synthesis from an activated alcohol
This reaction is driven by hydrolysis of PPi
Phosphatidylethanolamine can be
synthesized from CDP-ethanolamine
Phosphatidylcholine is the most common
phospholipid in humans
Dietary choline is activated in a series of
reactions analogous to those in the
activation of ethanolamine
Phosphatidylcholine may also be synthesized from
phosphatidylethanolamine when dietary choline is
insufficient
S-Adenosyl methionine is the methyl donor
Sphingolipids are synthesized from ceramide
b-N-acetyl
hexosaminidase
Tay Sachs disease results from the
inability to degrade a ganglioside
Cholesterol synthesis
Cholesterol maintains proper fluidity of cell membranes
and is the precursor of steroid hormones
De novo synthesis occurs predominantly in the liver
All 27 C atoms of cholesterol are derived from acetyl CoA
Synthesis begins with the formation of isopentenyl
pyrophosphate (IPP), an activated isoprene unit
Six molecules of IPP condense to form squalene
Squalene cyclizes to a tetracyclic product that is converted
to cholesterol
Isopentenyl pyrophosphate synthesis
The synthesis of mevalonate is the committed step in
cholesterol formation
2 NADPH + 2 H+
HMG-CoA
HMG-CoA
reductase
Mevalonate
Mevalonate is converted to an activated 5-carbon isoprene
Lovastatin is a competitive inhibitor of HMG-CoA reductase
Squalene synthesis
Squalene is synthesized from IPP
C5
C10
C15
C30
Squalene cyclization
Regulation of cholesterol synthesis
The rate of cholesterol synthesis is responsive to the cellular
levels of cholesterol
Cholesterol can be obtained from the diet or synthesized de
novo
A person on a low cholesterol diet will synthesize about
800 mg of cholesterol per day
Feedback inhibition is mediated primarily by changes in the
amount and activity of HMG CoA reductase
When cholesterol levels are high:
↓ Synthesis of reductase mRNA
↓ Translation of reductase mRNA
↑ Degradation of the reductase
↑ Phosphorylation of the reductase, decreasing activity
Plasma lipoproteins transport cholesterol and
triacylglycerols
Lipoproteins are
classified according to
increasing density
Lipoprotein metabolism
Low-density lipoproteins play a central role
in cholesterol metabolism
Familial hypercholesteremia is caused by failure of LDL
receptors and consequent high concentrations of
LDL cholesterol in the blood
Bile acids facilitate lipid absorption
Bile acids are synthesized in the liver from cholesterol, stored
and concentrated in the gall bladder and released into
the small intestine
7α-Hydroxylase
Liver
HMG CoA
Glucose
HMG CoA Reductase
Cholesterol
Levels
LDL Receptor
Cholesterol
Absorption
Blood Vessel
Small Intestines
LDL
Liver
HMG CoA
Glucose
HMG CoA Reductase
Cholesterol-7-hydroxylase
Cholesterol
Levels
LDL Receptor
Bile Acid
Pool
Blood Vessel
Re-absorption
Gall Bladder
Small Intestines
LDL
Steroid hormones are signaling molecules
that are synthesized from cholesterol
Progesterone (a progestagen) prepares the uterus for
implantation and the maintenance of pregnancy
Testosterone (an androgen) directs the development of male
secondary sex characteristics, including maintenance
of the testes and development of muscle mass (thus
testosterone is an anabolic steroid)
Estrogens (eg, estradiol) direct female female secondary sex
characteristics and participate in the ovarian cycle
Glucocorticoids (eg, cortisol) promote gluconeogenesis and
glycogen formation, enhance degradation of fat and
protein and inhibit the inflammatory response
Mineralocorticoids (eg aldosterone) regulate salt balance,
volume and pressure of the blood
Vitamin D is derived from cholesterol by the
energy of sunlight
Vitamin D plays an essential role in
calcium and phosphorous metabolism