Cholesterol Metabolism and Synthesis

Cholesterol Metabolism

• Normal blood cholesterol level is 150-200 mg%.
• Cholesterol is a lipid, a sterol, present in animal cell membranes, and essential for many biological processes.
• It's a component of cell membranes and necessary for synthesizing biologically important compounds.
• High cholesterol may lead to atherosclerotic vascular disease.
• Vegetable oils do not contain cholesterol.
• All sterols are derived from cholesterol.

Cholesterol Background Synthesis

• Cholesterol is obtained through diet and synthesis in many cells.
• It's synthesized primarily in the liver, intestines, adrenal cortex, testes, and ovaries.
• Humans synthesize approximately 1 gram of cholesterol daily.
• A typical western diet contains roughly 500 mg of cholesterol daily, primarily found in meat, eggs, and dairy products.
• Cholesterol synthesis begins with acetyl-CoA.

How is Cholesterol Synthesized?

• Cholesterol synthesis begins with precursor acetyl CoA which comes from pyruvate dehydrogenase (pyruvate to acetyl CoA) reactions, or from beta-oxidation of fatty acids, or from reactions breaking down amino acids.
• HMG-CoA synthase helps create HMG-CoA (β-hydroxymethylglutaryl-CoA).
• HMG-CoA reductase is the rate-limiting enzyme, and statins are competitive inhibitors of this enzyme for lowering cholesterol.
• Squalene (30 carbons) becomes cholesterol (27 carbons) via multiple steps and is synthesized in the cytosol and endoplasmic reticulum (ER) of the cell.

How is Cholesterol Synthesis Regulated?

• HMG-CoA reductase is inhibited by cholesterol, steroid hormones, glucagon, and glucocorticoids.
• It is stimulated by insulin and estrogen.
• Regulation involves feedback repression to prevent over-production.

Regulation by Sterol Regulatory Element-Binding Protein (SREBP)

• SREBPs are synthesized as inactive precursors in the endoplasmic reticulum.
• In low cholesterol conditions, SREBP cleavage activating protein (SCAP) escorts SREBPs to the Golgi where proteases cleave the SREBP.
• The NH2-terminal region of SREBPs binds to the sterol regulatory element, increasing transcription of LDL receptors and the HMG-CoA reductase and increasing cholesterol uptake and synthesis.

Synthesis of Compounds Requiring Cholesterol

• Bile acids (80% from cholesterol) are essential for the digestion and absorption of fats and lipids in the liver
• Steroid hormones (corticosteroids, mineralocorticoids, estrogens) are cholesterol-derived
• Vitamin D is synthesized from cholesterol
• Cholesterol is also a crucial component of cell membranes.
• Biliary cholesterol esters are formed through acyl-CoA:cholesterol acyltransferase and excess is stored as cholesterol esters.

Cholesterol and Various Conditions

• Diabetes: Insulin resistance or deficiency can increase lipolysis and free fatty acids in the blood, further increasing liver cholesterol synthesis, as well as impairing lipoprotein metabolism.
• Obstructive Jaundice: Blocked bile ducts disrupt bile flow, leading to increased cholesterol accumulation in the blood.
• Hypothyroidism: Lowered thyroid hormones can reduce LDL receptor activity, decreasing LDL clearance from the blood and thus increasing LDL accumulation.
• Nephrotic Syndrome: High protein loss in urine may increase liver lipoprotein production, resulting in elevated cholesterol.