BI4.1-8 | Chemistry and Metabolism of Lipids — Summary & Reflection

REFLECT

Think about what you ate today. Identify one source of saturated fat, one source of unsaturated fat, and one source of cholesterol in your meal.

Now trace the biochemical journey:

1. The dietary triglycerides were emulsified by bile acids, digested by pancreatic lipase, absorbed by enterocytes, and packed into chylomicrons for transport.
2. In your capillaries, lipoprotein lipase (activated by ApoCII) cleaved the triglycerides into fatty acids — taken up by your muscles for energy (beta-oxidation → acetyl-CoA → TCA cycle) or by adipose tissue for storage.
3. The chylomicron remnants went to your liver, which repackaged the cholesterol and new triglycerides into VLDL → released into blood → LPL → IDL → hepatic lipase → LDL.
4. LDL delivered cholesterol to your cells via LDL receptors. Excess LDL lingered in the blood...
5. Meanwhile, HDL scavenged cholesterol from your peripheral tissues (reverse cholesterol transport) and returned it to the liver.

Now consider: if your LDL receptor gene had a mutation (as in familial hypercholesterolaemia), at which step in this journey would the system fail — and what would happen to all the LDL that couldn't be cleared?

KEY TAKEAWAYS

Key takeaways — your study checklist:

1. Lipid classification — Simple (triglycerides, waxes), Compound (phospholipids, glycolipids, lipoproteins), Derived (fatty acids, cholesterol, prostaglandins). Lipids serve 4 roles: energy storage, structure, signalling, insulation.
2. Fatty acids — Saturated (no double bonds, solid), unsaturated (double bonds, liquid). Essential FAs: linoleic (omega-6) and α-linolenic (omega-3) — humans cannot make double bonds beyond C-9. Trans fats raise LDL, lower HDL.
3. Beta-oxidation — Mitochondrial matrix. Activation → carnitine shuttle (CPT-I rate-limiting, inhibited by malonyl-CoA) → 4-step spiral (oxidation, hydration, oxidation, thiolysis) → acetyl-CoA. Palmitate = 106 net ATP. MCAD deficiency → hypoketotic hypoglycaemia.
4. Lipogenesis — Cytoplasm. Citrate shuttle → ACC (rate-limiting, insulin activates, glucagon inhibits) → FAS uses NADPH → palmitate. Excess carbs → fat.
5. Cholesterol synthesis — HMG-CoA reductase (rate-limiting, STATINS inhibit). SREBP regulation. Cannot break steroid ring → excreted only as bile acids. Enterohepatic circulation.
6. Phospholipids — Amphipathic, form bilayers. Lecithin in surfactant (L/S ratio). Phosphatidylserine = apoptosis signal. Sphingolipidoses: Tay-Sachs, Niemann-Pick, Gaucher.
7. Lipoproteins — Chylomicrons (dietary TG, gut), VLDL (endogenous TG, liver), LDL ('bad', delivers cholesterol, ApoB-100, LDL receptor uptake), HDL ('good', reverse cholesterol transport, ApoA-I). Lp(a) — genetically determined, high in Indians.
8. Atherosclerosis — Endothelial injury → LDL infiltration → oxidation → scavenger receptor uptake → foam cells → fatty streak → plaque → rupture → thrombus → MI/stroke.
9. Dyslipidaemias — FH (LDL receptor defect, most common, tendon xanthomas, premature MI). Type IV (↑ TG, pancreatitis risk). Type I (LPL/ApoCII deficiency, lipaemia).
10. Lipid-lowering drugs — Statins (↓ HMG-CoA reductase → ↑ LDL receptors → ↓ LDL 30-50%), Fibrates (PPARα → ↓ TG), Ezetimibe (↓ absorption), PCSK9i (↓ LDL receptor degradation → ↓ LDL 50-70%).