Substrates for lipid synthesisPhosphatidate 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 synthesisLiver TAGs are transported to muscle for use as fuel or to adipose tissue for storage

Phospholipid synthesisPhosphatidate is also a precursor for phospholipids

Phospholipid synthesis combines diacylglyceride with an alcohol, one of the components must be activated

Choline

Ethanolamine

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

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

Synthesis from an activated alcohol

This reaction is driven by hydrolysis of PPi

Phosphatidylcholine may also be synthesized from phosphatidylethanolamine when dietary choline is insufficient

S-Adenosyl methionine is the methyl donor

Sphingolipids are synthesized from ceramide

Tay Sachs disease results from theinability to degrade a ganglioside

b-N-acetylhexosaminidase

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

HMG-CoAreductase

Isopentenyl pyrophosphate synthesisThe synthesis of mevalonate is the committed step in cholesterol formation

Mevalonate is converted to an activated 5-carbon isoprene

HMG-CoA Mevalonate

2 NADPH + 2 H+

Lovastatin is a competitive inhibitor of HMG-CoA reductase

Squalene synthesis

Squalene is synthesized from IPPC5 C10 C15 C30

Squalene cyclization

Regulation of cholesterol synthesisThe 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 andtriacylglycerols

Lipoproteins are classified according to

increasing density

Lipoprotein metabolism

Low-density lipoproteins play a central rolein cholesterol metabolism

Familial hypercholesteremia is caused by failure of LDLreceptors 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

Cholesterol Levels

GlucoseHMG CoA

HMG CoA Reductase

LDL Receptor

Blood Vessel

LDL

Liver

Small Intestines

Cholesterol Absorption

Cholesterol Levels

GlucoseHMG CoA

HMG CoA Reductase

LDL Receptor

Blood Vessel

LDL

Liver

Small Intestines

Bile Acid Pool

Cholesterol-7- -hydroxylase

Gall Bladder

Re-absorption

Steroid hormones are signaling molecules that are synthesized from cholesterol

Progesterone (a progestagen) prepares the uterus for implantation and the maintenance of pregnancyTestosterone (an androgen) directs the development of male

secondary sex characteristics, including maintenanceof the testes and development of muscle mass (thustestosterone is an anabolic steroid)

Estrogens (eg, estradiol) direct female female secondary sex characteristics and participate in the ovarian cycle

Glucocorticoids (eg, cortisol) promote gluconeogenesis andglycogen 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 theenergy of sunlight

Vitamin D plays an essential role in calcium and phosphorous metabolism