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
- Acetate condensation: Three molecules of acetate → 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA).
- Rate-limiting step: HMG-CoA → mevalonic acid, catalyzed by HMG-CoA reductase.
- Statins (HMG-CoA reductase inhibitors) ↓ cholesterol biosynthesis → ↓ serum cholesterol.
- 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.
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
- Chylomicrons
- Large, low-density particles carrying dietary lipid.
- Apolipoproteins: apo A (I, II, IV), apo B48, apo C (I, II, III), apo E.
- Very Low-Density Lipoprotein (VLDL)
- Mainly transports triglycerides.
- Apolipoproteins: apo B100, apo C (I, II, III), apo E.
- Low-Density Lipoprotein (LDL)
- Transports primarily cholesterol esters.
- Apolipoprotein: apo B100.
- 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.
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.
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
- Familial Hypercholesterolemia (FH)
- Autosomal dominant, LDL receptor mutations.
- ↑ plasma LDL cholesterol, ↑ CHD risk.
- Familial Defective apo B100
- apo B100 mutation → defective LDL receptor binding → ↑ LDL.
- Familial Dysbetalipoproteinemia (Type III)
- apo E2/E2 → defective chylomicron/VLDL remnant clearance → ↑ cholesterol + ↑ triglycerides.
- Elevated Lipoprotein(a)
- Covalent bond of apo B100 to Lp(a), impairs fibrinolysis → ↑ CHD risk.
- Polygenic Hypercholesterolemia
- Multiple genetic/environmental factors, borderline-high or high LDL, increased CHD risk.
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
- Nascent/precursor HDL (apo AI, phospholipids) formed in liver/intestine.
- HDL accepts free cholesterol from cells or TGRLs (chylomicrons, VLDL).
- LCAT (activated by apo AI) esterifies free cholesterol → cholesteryl esters → moves to HDL core → HDL2 forms.
- Cholesteryl ester transfer protein (CETP) exchanges cholesteryl esters in HDL2 for triglycerides in TGRLs.
- Depleted HDL2 can become HDL3 via hepatic lipase hydrolysis of extra triglycerides.
- 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.