Cholesterol Metabolism - Full Explanation

The diagram covers three major pathways: the exogenous pathway (dietary fat), the endogenous pathway (liver-derived lipoproteins), and reverse cholesterol transport (HDL system). Each pathway is described below.

1. Exogenous Pathway (Dietary Fat / Chylomicrons)

What happens: Dietary fat absorbed from the gut gets packaged into large lipoprotein particles called chylomicrons and delivered to peripheral tissues.

Step-by-step:

Step	Event
1	Dietary fat is absorbed in the small intestine lumen by intestinal cells (enterocytes).
2	Inside the enterocyte, the MTTP gene (Microsomal Triglyceride Transfer Protein) loads triglycerides (TG) onto a protein scaffold called ApoB48 to form a nascent chylomicron. This particle enters the systemic circulation via lymphatics.
3	In circulation, the chylomicron picks up ApoE and ApoCII donated by HDL.
4	ApoCII activates Lipoprotein Lipase (LPL), which sits on the walls of capillaries (attached by heparin, upregulated by PPARα). LPL hydrolyzes the TG core of the chylomicron, releasing free fatty acids (FFAs).
5	FFAs are taken up by adipocytes (for fat storage) and muscle cells (for energy).
6	The shrunken, TG-depleted particle is now a chylomicron remnant, which carries mostly cholesteryl esters and retains ApoE.
7	ApoE on the remnant is recognized by ApoE receptors on hepatocytes, and the remnant is endocytosed and cleared by the liver.

Handwritten note - Lomitapide: This drug inhibits MTTP, preventing chylomicron assembly inside the intestinal cell. Fat accumulates as "fat globules in the intestine" and cannot enter the blood. It is used in homozygous familial hypercholesterolemia (HoFH) and reduces LDL-C and ApoB by up to 40%. - Fuster and Hurst's The Heart, 15th Edition

2. Endogenous Pathway (Liver to Peripheral Tissues via VLDL → IDL → LDL)

What happens: The liver synthesizes its own lipoprotein particle (VLDL) to export cholesterol and triglycerides to the body.

Step-by-step:

Step	Event
1	The hepatocyte assembles VLDL, loading it with TG + cholesteryl esters (Chol E) + ApoB100.
2	In circulation, LPL (same enzyme as above, activated by ApoCII from HDL) strips TG from VLDL, shrinking it into IDL (Intermediate-Density Lipoprotein).
3	Hepatic lipase further removes TG from IDL, converting it to LDL (Low-Density Lipoprotein), which is now cholesterol-rich and TG-poor.
4	LDL carries ApoB100 on its surface. ApoB100 is the ligand that binds to LDL receptors on peripheral cells and hepatocytes.
5	LDL is taken up by receptor-mediated endocytosis via LDL receptors, delivering cholesterol to cells.

Handwritten note - ApoB100 = marker of LDL receptors. ApoB100 is what LDL receptors "see" to pull LDL out of the circulation.

3. Reverse Cholesterol Transport (HDL Pathway)

What happens: HDL scavenges excess cholesterol from peripheral tissues and returns it to the liver. This is why HDL is "good cholesterol."

Step	Event
1	Nascent HDL is synthesized by the liver and intestine. It is discoidal (flat, amphipathic) and carries ApoA1 and ApoCII and ApoE.
2	Nascent HDL absorbs free cholesterol from peripheral cell membranes via ABCA1 transporter.
3	LCAT (Lecithin-Cholesterol AcylTransferase) is activated by ApoA1. It esterifies free cholesterol into cholesteryl ester (Chol E), which moves into the hydrophobic core of the HDL particle. The particle becomes spherical = Mature HDL.
4	CETP (Cholesteryl Ester Transfer Protein) swaps the cholesteryl esters from HDL into VLDL, IDL, and LDL in exchange for TG. This funnels cholesterol back into the endogenous pathway, where LDL receptors eventually clear it from the blood. - Harrison's Principles of Internal Medicine 22E

4. Apolipoprotein Summary (from the reference box in the diagram)

Apoprotein	Lipoprotein Carried On	Function
ApoA1	HDL	Activates LCAT
ApoB48	Chylomicron	Structural protein; marks chylomicron origin (intestine)
ApoB100	VLDL → IDL → LDL	Ligand for LDL receptor ("marker of LDL receptors")
ApoCII	Chylomicron, VLDL	Activates Lipoprotein Lipase ("cuts and cleaves" TG)
ApoE	Chylomicron remnant, IDL	Remnant marker; binds ApoE receptors on hepatocytes

5. Key Pharmacological Annotations (Handwritten Notes)

Drug/Molecule	Target	Effect
Lomitapide	MTTP inhibitor	Blocks chylomicron assembly in enterocytes; fat globules accumulate in intestine; used in HoFH
Heparin	Releases LPL from endothelium	Makes LPL available in blood (used in IV heparin challenge to measure LPL activity)
PPARα	Nuclear receptor	Transcription factor that upregulates LPL gene expression

Big Picture Summary

Diet → Chylomicron (ApoB48) → LPL strips TG → Remnant → Liver
Liver → VLDL (ApoB100) → LPL/HL → IDL → LDL → LDL receptor on cells
Peripheral cells → Nascent HDL → LCAT (ApoA1) → Mature HDL → CETP → Back into VLDL/LDL → Liver

The liver is the central hub: it receives remnants and LDL, synthesizes VLDL, and secretes nascent HDL. All roads in lipid metabolism lead back to the hepatocyte.

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