1. CHOLESTEROL BIOSYNTHESIS

2. BIOSYNTHESIS OF CHOLESTEROL
Cholesterol is doubtless the most publicized lipid, notorious because of the strong correlation between high levels of cholesterol in the blood and the incidence of human cardiovascular diseases.
It plays an crucial role as a component of cellular membranes and as a precursor of steroid hormones and bile acids.
Cholesterol is an essential molecule in many animals, including humans, but is not required in the mammalian diet-all cells can synthesize it from simple precursors.
The structure of this 27-carbon compound is formed from acetyl-coA in a complex series of reactions ,through the

3. Intermediates ß-hydroxy-ß-methylglutaryl-coA, mevalonate,and two activated isoprenes,dimethylallyl pyrophosphate and isopentyl pyrophosphate. Condensation of isoprene units produces the non-cyclic squalene, which is cyclized to yeild the steroid ring system and side chain.
Synthesis takes place in 4 stages,
Condensation of three acetate units to form a six carbon intermediate, mevalonate;
Conversion of mevalonate to activated isoprene units;
Polymerization of six 5 carbon isoprene units to form the 30-carbon linear squalene; and
Cyclization of squalene to form the four rings of the steroid nucleus, with further series of changes to produce CHOLESTEROL.

10. CHOLESTEROL HAS SEVERAL FATES
Much of the cholesterol synthesis in vertebrates takes place in liver.
A small fraction of the cholesterol made there is incorporated into the membranes of hepatocytes, but most of it is exported in one of three forms: biliary cholesterol, bile acids, or cholesteryl esters.
Bile acids and their salts are relatively hydrophillic cholesterol derivatives that are synthesized in the liver and aid in the lipid digestion.
Cholesteryl esters are formed in the liver through the

11. action of acyl-coA-cholesterol acyl transferase (ACAT)
action of acyl-coA-cholesterol acyl transferase (ACAT). This enzyme catalyses the transfer of a fatty acid from coenzyme A to the hydroxyl group of cholesterol, converting the cholesterol to a more hydrophobic form.
Cholesteryl esters are transported in secreted lipoprotein particles to other tissues that use cholesterol, or they are stored in the liver.

12. All growing animal tissues need CHOLESTEROL for membrane synthesis, and some organs (adrenal gland and gonads, for example).
Use CHOLESTEROL as a precursor for steroid hormone production
CHOLESTEROL is also a precursor of vitamin D.

14. REGULATION OF CHOLESTEROL BIOSYNTHESIS
Cholesterol synthesis is a complex and energy expensive process, so it is advantageous to an organism to complement dietary intake.
In mammals, cholesterol production is regulated by intracellular cholesterol concentration and by the hormones glucagon and insulin.
Regulation is mediated by an elegant system of transcriptional regulation of the gene encoding HMG-CoA reductase.
This gene, along with more than 20 other genes encoding enzymes that mediate the uptake and synthesis of

15. Cholesterol and unsaturated fatty acids, is controlled by a small family of protein called sterol regulatory element-binding protein (SREBPs).
Newly synthesized proteins are embedded in the ER.
Only soluble amino terminal domain of an SREBP functions as a transcriptional activator.
To activate transcription of the HMG-CoA reductase and other genes, the transcriptionally active domain is separated from SREBP by proteolytic cleavage.
When cholesterol levels are high, SREBPs are inactive, secured to ER in a complex with another protein called SREBP cleavage- activating protein (SCAP).
SCAP binds cholesterol and a number of other sterols, thus acting as a sterol sensor.

16. When sterol levels are high, the SCAP-SREBP complex interact with another protein that retains the entire complex in ER.
When the levels declines, conformational change in SCAP causes the release of the complex from ER and it migrates to golgi complex.
In golgi complex, SREBP is cleaved twice by two different proteases.
The second cleavage releases the amino- terminal domain into the cytosol.
The domain travels to the nucleus and activates transcription of its target gene.
The domain of SREBP has a shorter half-life and is rapidly degraded by proteosomes.

18. When sterol level increases, the proteolytic release of SREBP domains is again blocked, and proteosome degradation of the existing active domains results in rapid shut down of the gene targets.
Hormonal control is mediated by covalent modification of HMG-CoA reductase itself.
Glucagon stimulates phosphorylation (inactivation), and insulin promotes dephosphorylation, activating the enzyme and favoring cholesterol synthesis.

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