Lipoprotein Metabolism – Exam-Review Notes

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• Topic: Lipoprotein Metabolism (transport & fate of TAG, CE, PL)

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• Lipids circulate as lipoproteins: chylomicrons, VLDL, LDL, HDL.
• Function = solubilize dietary & hepatic lipids for plasma transport.

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• Spherical particles: hydrophobic core (TAG, CE); surface (PL head-groups, free C, apolipoproteins).
• Differences lie in lipid-to-protein ratio → size & density gradient.

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• Core = TAG + CE; surface = PL, unesterified C, apolipoproteins.

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• Neutral-lipid core + amphipathic shell; >$80\%$ TAG in chylomicron mass.

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• Density order (g mL$^{-1}$): CM $<0.95$ < VLDL $0.95!{-}!1.006$ < IDL $1.006!{-}!1.019$ < LDL $1.019!{-}!1.063$ < HDL $>1.063$.
• TAG richest = CM; Protein richest = HDL.

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• Size ↓ & density ↑ from CM → HDL.

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• Separation: ultracentrifugation by density; electrophoresis by charge/mobility.

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• Electron microscopy confirms four distinct classes.

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• Apolipoproteins: bind lipids, target receptors, activate enzymes; some are structural (non-exchangeable).

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• Major apolipoproteins:
– A-I: HDL; activates LCAT.
– A-II/A-IV: HDL functions.
– B-48: structural in CM (no LDL-R binding).
– B-100: structural in VLDL→LDL; binds LDL-R.

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• C-II activates LPL; C-III inhibits LPL; E binds hepatic receptors; CETP & apo(a) are additional components.

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• Chylomicron (CM) assembly in enterocyte: microsomal TAG transfer protein loads lipids onto apoB-48 → nascent CM enters lymph → blood.
• Gains apoE & apoC (from HDL) in plasma.

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• Enterocyte pathway: resynthesis in SER → packaging in Golgi → CM exocytosis to lacteal.

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• CM: >80\% mass TAG; surface apoB-48, C-II, C-III, E act as metabolic signals.

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• ApoC-II activates capillary LPL → FFA release.
• FFA fate: oxidation (muscle) or re-esterification (adipose).
• Insulin ↑ LPL synthesis (especially adipose); heart LPL has low $K_m$.

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• Unused FFA carried by albumin.
• LPL anchored by heparan sulfate.
• LPL or apoC-II deficiency → type I hypertriacylglycerolemia (CM accumulation).

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• CM remnants (TAG-depleted, rich in CE, apoE, B-48) bind hepatic apoE receptors → endocytosis → lysosomal degradation.

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• Liver removes CM remnants; provides cholesterol & TAG for VLDL synthesis.

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• VLDL: produced by liver; deliver endogenous TAG to tissues via LPL.
• Excess dietary CHO/fat → TAG synthesis → VLDL export.

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• ApoB-100 synthesized in RER; lipids added in SER & Golgi → nascent VLDL enters blood.

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• Plasma maturation: VLDL receives apoC & apoE from HDL.
• LPL removes TAG → IDL (VLDL remnant).
• ApoC returns to HDL.
• Fate: IDL taken up by liver (apoE) or remodeled to LDL.

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• CETP swaps HDL CE ↔ VLDL TAG → promotes LDL formation.

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• Summary: CM & VLDL both deliver TAG via LPL; remnants cleared by liver.

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• LDL: CE-rich; main apo = B-100; delivers cholesterol to peripheral cells via LDL-R.
• LDL-R defects → familial hypercholesterolemia (type II) → atherosclerosis.

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• LDL-R in clathrin-coated pits; receptor–LDL complex endocytosed → endosome acidification releases LDL; receptor recycled; LDL degraded in lysosome → free C, FA, amino acids.

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• Intracellular cholesterol:
– ↓ HMG-CoA reductase (cholesterol synthesis).
– ↓ LDL-R synthesis.
– ↑ ACAT → CE storage.
• Regulation via SREBP system.

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• HDL genesis: liver/intestine secrete nascent discoidal HDL (apoA-I).
• HDL accepts cholesterol from tissues; LCAT (activated by A-I) esterifies it → HDL3 → HDL2.

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• Reverse cholesterol transport: HDL conveys cholesterol to liver (direct via SR-B1 receptor) or to other lipoproteins via CETP.

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• HDL-C inversely correlates with CVD risk (“good” cholesterol).
• SR-B1 mediates selective CE uptake; HDL particle recycled.

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• CETP moves $\approx1/3$ HDL CE to VLDL/LDL in exchange for TAG (indirect reverse transport).

Page 44–47 (Lipid profile)

• Total C: desired $<200\,\text{mg dL}^{-1}$; high risk $\ge240$. • HDL-C: protective $>60$; high risk <40 (men) / <50 (women).
• LDL-C: optimal <100; high risk $160{-}189$; very high $\ge190$.
• TAG: normal <150; high $200{-}499$; very high $\ge500$.

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• Dyslipidaemia: hypertriacylglycerolemia, hypercholesterolemia.
• Etiology = genetic enzyme/apo defects or secondary metabolic disease.

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• End of content / Q&A.