STEPTRACKERBIOCHEMISTRY + PHARMACOLOGY + CARDIOLOGY | LIPID METABOLISM | HIGH-YIELD REVIEW

Cholesterol & Lipoproteins

Cholesterol synthesis and its drug targets, the apolipoproteins that address each particle, and the path from chylomicron to LDL to HDL.

FOCUS ON
HMG-CoA reductase (rate-limiting; statins) makes mevalonate. Particles: chylomicrons (dietary TG, intestine), VLDL (hepatic TG), IDL, LDL (cholesterol to tissues), HDL (reverse transport to liver). Key apos: B-48 (chylomicron secretion), B-100 (VLDL/LDL, binds LDL receptor), C-II (activates LPL), E (remnant uptake), A-I (activates LCAT). LPL on capillaries frees TG fatty acids; LCAT esterifies HDL cholesterol; CETP trades HDL cholesteryl ester for TG.
ITEM
ROLE
WHERE
CLUE · DRUG
HMG-CoA reductase
rate-limiting
HMG-CoA → mevalonate → … squalene → cholesterol
Liver (SER/cytosol); ↑ by insulin; ↓ by cholesterol (SREBP)
Statins → ↑ LDL receptors · myopathy, hepatotoxicity
Cholesterol uses
Membranes, bile acids (7α-hydroxylase, rate-limiting), steroid hormones, vitamin D
Liver, adrenal, gonads, skin
Bile acid sequestrants pull cholesterol into bile
Chylomicrons
Carry dietary TG and cholesterol from gut via lymph
ApoB-48, C-II, E
Milky plasma after a fatty meal
VLDL
Carries hepatic TG to tissues
ApoB-100, C-II, E
↑ In insulin resistance, alcohol
IDL
VLDL remnant; to liver (ApoE) or → LDL
ApoB-100, E
↑ In dysbetalipoproteinemia (ApoE2)
LDL
Delivers cholesterol to tissues via LDL receptor (receptor-mediated endocytosis, clathrin)
ApoB-100
"Lethal" — atherosclerosis · PCSK9 degrades LDL receptors (evolocumab blocks)
HDL
Reverse cholesterol transport from tissues to liver; apo reservoir
ApoA-I (activates LCAT), C-II, E
"Healthy" · ↑ by exercise, alcohol, niacin, estrogen
Lipoprotein lipase
Hydrolyzes TG in chylomicrons/VLDL on capillary endothelium (fat, muscle)
Activated by ApoC-II
Deficiency → type I hyperchylomicronemia
Hepatic lipase · HSL
Hepatic lipase: degrades TG in IDL/HDL · hormone-sensitive lipase: adipose TG → FFA (fasting)
Liver · adipocytes
HSL ↑ by epinephrine, ↓ by insulin
LCAT · CETP
LCAT esterifies free cholesterol in HDL · CETP moves cholesteryl esters from HDL to VLDL/IDL/LDL
Plasma
LCAT deficiency → corneal opacities ("fish-eye")
Ezetimibe · fibrates · niacin
Ezetimibe blocks NPC1L1 (gut absorption) · fibrates activate PPAR-α (↑ LPL, ↓ TG) · niacin ↓ VLDL secretion
—
Fibrates + statins → myopathy risk

Picture it — lipoprotein traffic

GutChylomicronB-48 · C-II · ELPLRemnantELIVERVLDLB-100 · C-II · ELPLIDLHLLDLB-100LDL receptortissues + liverHDLA-I (LCAT)tissue cholesterol →C-II activates LPL · E clears remnants · B-100 binds LDL receptor
From gut and liver to tissuesChylomicrons carry dietary fat; VLDL carries liver-made fat. LPL (with ApoC-II) unloads triglyceride; remnants return to the liver via ApoE; LDL delivers cholesterol via the LDL receptor; HDL brings cholesterol back.

Schematic diagrams, not to scale.

Mechanism — the lipoprotein loop

Gut → chylomicronB-48
→
LPL (C-II)TG → FFA to tissues
→
Chylomicron remnant→ liver (ApoE)
Liver → VLDLB-100
→
LPL→ IDL
→
Hepatic lipase→ LDL
→
LDL receptor (B-100)Tissues, liver
HDLPicks up tissue cholesterol (ABCA1)
→
LCAT (A-I)Esterifies
→
CETP / SR-B1→ liver

Apolipoprotein address labels

APO
FUNCTION
ON
A-I
Activates LCAT
HDL, chylomicron
B-48
Chylomicron assembly/secretion
Chylomicron
B-100
Binds LDL receptor
VLDL, IDL, LDL
C-II
LPL cofactor
Chylomicron, VLDL, HDL
E
Remnant uptake
All except LDL

How it's tested

COMMON CONFUSIONApoB-48 and B-100 come from one gene; RNA editing in the gut creates a stop codon for the shorter B-48.
THE TRAPLDL lacks ApoE — it's cleared only through B-100 binding the LDL receptor. Remnants (chylomicron, IDL) need ApoE.
YOUR APPROACHParticle → its apos → enzyme acting on it → where it goes → disease when that step fails (10.04) → drug that targets it.

If you see… think…

Rate-limiting enzyme of cholesterol synthesis → HMG-CoA reductase
Rate-limiting enzyme of bile acid synthesis → 7α-hydroxylase
Apo that activates lipoprotein lipase → C-II
Apo binding the LDL receptor → B-100
Apo mediating remnant uptake by liver → E
Apo that activates LCAT → A-I
Particle with B-48 only → chylomicron
Antibody drug raising LDL receptor numbers by blocking degradation → PCSK9 inhibitor
Drug blocking intestinal cholesterol absorption → ezetimibe (NPC1L1)
Corneal clouding + low HDL → LCAT deficiency