Cholesterol Metabolism

CHOLESTEROL SYNTHESIS AND METABOLISM

Structure and Roles of Cholesterol

• 4-ring hydrocarbon structure with an 8-carbon side chain.
• Key component of cell membranes.
• Substrate for steroid hormones and bile acids.

Sources of Cholesterol

• Endogenous synthesis in the liver and other tissues.
• Exogenous ingestion of animal fats (e.g., meat, eggs, dairy).

Biosynthesis Pathway

1. Acetate condensation: Three molecules of acetate → 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA).
2. Rate-limiting step: HMG-CoA → mevalonic acid, catalyzed by HMG-CoA reductase.
   • Statins (HMG-CoA reductase inhibitors) ↓ cholesterol biosynthesis → ↓ serum cholesterol.
3. Mevalonic acid → cholesterol through multiple enzymatic steps.

Cholesterol Metabolism and Excretion

• Excreted into the bile as free cholesterol or converted to bile acids.
• Enterohepatic circulation:
  • ~50% of biliary cholesterol and ~97% of bile acids are reabsorbed in the small intestine and returned to the liver.
  • The remainder is excreted in feces.

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LIPOPROTEIN OVERVIEW

Composition

• Macromolecules containing:
  • Protein (apolipoproteins, “apo”),
  • Triglycerides,
  • Cholesterol esters,
  • Free cholesterol.
• Function: Transport dietary and endogenous lipids (cholesterol, triglycerides) in the blood.

Classes of Lipoproteins

1. Chylomicrons
   • Large, low-density particles carrying dietary lipid.
   • Apolipoproteins: apo A (I, II, IV), apo B48, apo C (I, II, III), apo E.
2. Very Low-Density Lipoprotein (VLDL)
   • Mainly transports triglycerides.
   • Apolipoproteins: apo B100, apo C (I, II, III), apo E.
3. Low-Density Lipoprotein (LDL)
   • Transports primarily cholesterol esters.
   • Apolipoprotein: apo B100.
4. High-Density Lipoprotein (HDL)
   • Transports mainly cholesterol esters.
   • Apolipoproteins: apo A (I, II), apo C (I, II, III), apo E.

Apolipoprotein Functions

• apo AI: Structural protein of HDL, activates LCAT (lecithin–cholesterol acyltransferase).
• apo AII: Structural protein of HDL, activates hepatic lipase.
• apo AIV: Activator for lipoprotein lipase (LPL) and LCAT.
• apo B100: Structural protein for VLDL and LDL; ligand for LDL receptor.
• apo B48: Required for chylomicron formation and secretion.
• apo CI: Activates LCAT.
• apo CII: Key cofactor for LPL (triglyceride hydrolysis).
• apo CIII: Inhibits LPL.
• apo E: Ligand for VLDL/chylomicron remnant receptor; three isoforms (E2, E3, E4). Homozygous E2 → familial dysbetalipoproteinemia (Type III hyperlipidemia).

LDL Receptor and Cholesterol Homeostasis

• LDL receptor mediates endocytosis of apo B– or apo E–containing lipoproteins (LDL, chylomicron remnants, VLDL).
• LDL receptor expression is regulated based on cellular cholesterol levels.

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GASTROINTESTINAL ABSORPTION OF CHOLESTEROL AND TRIGLYCERIDES

Dietary Fat Digestion

• Starts in stomach (gastric peristalsis, mixing, gastric lipase).
• Primarily completed in the small intestine.
• Triglycerides → free fatty acids + monoglycerides by pancreatic lipase.
• Bile salts form micelles → facilitate transport to enterocytes.

Enterocyte Uptake and Chylomicron Formation

• Long-chain fatty acids re-esterified into triglycerides in smooth ER.
• Cholesterol esterified by cholesterol acyltransferase.
• Assembly with apo proteins (apo B48) → chylomicrons in the Golgi.
• Chylomicrons exit enterocytes → lymphatics → thoracic duct → bloodstream.

Intravascular Metabolism

• Chylomicrons obtain apo C and apo E in circulation.
• Lipoprotein lipase (LPL) in muscle/adipose/breast tissue breaks down chylomicron triglycerides.
• Remnants taken up by liver via apo E recognition.

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REGULATION OF LDL RECEPTOR AND CHOLESTEROL CONTENT

Key Points

• Plasma LDL (cholesterol) mainly cleared by the LDL receptor.
• ~75% of LDL uptake occurs in the liver.
• Sterol regulatory element–binding protein (SREBP) modulates LDL receptor gene expression and HMG-CoA reductase.
• Intracellular cholesterol up → ↓ LDL receptors, ↓ HMG-CoA reductase, ↑ cholesterol storage via ACAT.

Common Genetic Dyslipidemias

1. Familial Hypercholesterolemia (FH)
   • Autosomal dominant, LDL receptor mutations.
   • ↑ plasma LDL cholesterol, ↑ CHD risk.
2. Familial Defective apo B100
   • apo B100 mutation → defective LDL receptor binding → ↑ LDL.
3. Familial Dysbetalipoproteinemia (Type III)
   • apo E2/E2 → defective chylomicron/VLDL remnant clearance → ↑ cholesterol + ↑ triglycerides.
4. Elevated Lipoprotein(a)
   • Covalent bond of apo B100 to Lp(a), impairs fibrinolysis → ↑ CHD risk.
5. Polygenic Hypercholesterolemia
   • Multiple genetic/environmental factors, borderline-high or high LDL, increased CHD risk.

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HIGH-DENSITY LIPOPROTEIN METABOLISM AND REVERSE CHOLESTEROL TRANSPORT

HDL Structure

• Composed of ~50% lipid (phospholipids, cholesteryl esters, free cholesterol, triglycerides) + ~50% protein (apo AI, apo AII, others).
• Main subclasses: HDL2, HDL3, minor HDL1.

Reverse Cholesterol Transport

1. Nascent/precursor HDL (apo AI, phospholipids) formed in liver/intestine.
2. HDL accepts free cholesterol from cells or TGRLs (chylomicrons, VLDL).
3. LCAT (activated by apo AI) esterifies free cholesterol → cholesteryl esters → moves to HDL core → HDL2 forms.
4. Cholesteryl ester transfer protein (CETP) exchanges cholesteryl esters in HDL2 for triglycerides in TGRLs.
5. Depleted HDL2 can become HDL3 via hepatic lipase hydrolysis of extra triglycerides.
6. SR-B1 (scavenger receptor B1) mediates selective uptake of cholesteryl esters into adrenal, gonadal, liver cells.

Clinical Relevance

• HDL is antiatherogenic:
  • Removes cholesterol from cells (incl. arterial walls).
  • Paraoxonase enzyme on HDL inhibits LDL oxidation.
• Inversely correlated with CHD risk (higher HDL = lower risk).
• Tangier disease: ABCA1 mutation → low HDL due to poor free cholesterol/phospholipid transfer to apo AI.