Cholesterol Synthesis

Question 1

Describe the properties of cholesterol and discuss why cholesterol is important.

Answer 1

• Mainly to make bile acids for digestion
• Planar hydrophobic ring and aliphatic side chain. Amphipathic becuase of polar OH group.
• Stable and chemically inert
• Found in membranes, lipoproteins, all tissues
• Precursor to steroid hormones, vitamin D, bile acids

Question 2

Describe the sources of cholesterol (dietary and de novo synthesis) and discuss the role of bile acids in cholesterol metabolism

Answer 2

• Major bile acids: cholic acid, chenodeoxycholic acid. Made in the liver from cholesterol and stored in the gall bladder.
• Enterohepatic circulation-recycled form intestine to liver (98% efficient)
• Role: emulsifies lipids in the diet
• From diet: from most animal tissues

Question 3

Discuss when and where de novo cholesterol synthesis occurs in the body.

Answer 3

• Mainly in the liver and some in intestines. In the cytoplasm of cell. In well fed state in all tissues. Regulated by diet/hormones.
• Acetyl coA→HMG-CoA→ Mevalonic Acid
• Can be made out of anything that’s broken down to acetyl CoA –carbs, lipids, proteins
• Recognize: 3 hydroxy-3methyl glutaryl CoA. Catalyzes rate limited state above in bold. (HMG coA reductase)

Question 4

Identify the precursors of cholesterol synthesis.

Answer 4

• Acetyl coA

* NADPH

Question 5

Name the enzyme that catalyzes the rate-limiting step in cholesterol synthesis.

Answer 5

HMG coA Reductase

Question 6

Discuss the regulation of cholesterol synthesis.

Answer 6

• Regulated by phophorylation and dephophoraylation of HMG coA by AMP activated kinase. Like FA synthesis
• Diet, hormones,
• Targeted by cholesterol lowering drugs: statins. Statins mimic HMG coA.
• SREBP involved in synthesis and degradation of HMG coA reductase. SREBP=sterol receptor element binding protein. It becomes a transcription activating factor for HMG coA reductase and LDL receptor.
• Liver cholesterol synthesis regulated by uptake of HDL IDL, and chylomicron remnants, and bile acids
• Non hepatic cholesterol regulated by uptake of LDL

Question 7

Describe how cholesterol is transported between tissues.

Answer 7

• Lipoproteins –particles in blood made out of molecules. (serum lipoprotein)
• Lipoproteins: Chylomicron>VLDL>IDL>LDL>HDL (by size and density)
• Atherogenic particles: VLDL, IDL, LDL-forming plaque
• Chylomicron about size of bacteria, smaller than RBCs
• Structure: consist of lipids and amorphous proteins. Proteins (Apo proteins), cholesterol, and phospholipids on surface, TAGs and cholesterol esters in center
• Chylomicrons produced in intenstine and VLDL in liver, converted to other proteins

Question 8

Recognize the names of intermediates in cholesterol synthesis: mevalonic acid, isopentenyl pyrophosphate (PP), geranyl PP, farnesyl PP, squalene, lanosterol

Answer 8

mevalonic acid, isopentenyl pyrophosphate (PP), geranyl PP, farnesyl PP, squalene, lanosterol

Question 9

Name substances that are made from cholesterol in the body.

Answer 9

• Steroid hormones
• Bile acids
• Substrates for posttranslational protein modifications (prenylation): farnesylation (farnesyl PP) and geranylgeranylation (geranyl PP)
• Heme A synthesis
• Coenzyme Q
• Vitamin D3
• Carrier molecule for posttranslational glycosylation of proteins (in Golgi): Dolichol P (polyprenol, C80-100), also a biomarker for aging