I-12. Dyslipidemias; primary hyperlipoproteinemia syndromes

脂質異常症の分類；原発性高リポタンパク血症

Lipoproteins — Composition & Classification

Lipoproteins transport insoluble lipids: a hydrophobic core (cholesterol esters, triglycerides/TAG) surrounded by a hydrophilic surface (free cholesterol, phospholipids, apolipoproteins).
Classes (by density / lipid / apolipoproteins / source):
- Chylomicron — TAG; ApoB-48, A/C/E; from intestine. Lowest density but largest particle.
- VLDL — TAG; ApoB-100, C, E; from liver.
- IDL — cholesterol ester; ApoB-100, E, C; from VLDL catabolism.
- LDL — cholesterol ester; ApoB-100; from IDL catabolism. Main blood cholesterol carrier.
- HDL — CE/phospholipid; ApoA, C, E; liver/intestine.

Lipoprotein Metabolism

Chylomicron (exogenous/dietary transport)

Intestinal cells secrete nascent, TAG-rich chylomicrons.
Acquire ApoB-48, ApoC-II, ApoE from HDL → mature chylomicron.
Lipoprotein lipase (adipose/muscle capillaries) degrades TAG → returns ApoC to HDL → chylomicron remnant.
Fatty acids stored in adipose; remnant taken up by liver via ApoE-mediated endocytosis.

VLDL → IDL → LDL (endogenous transport)

Liver secretes nascent VLDL (TAG-rich, ApoB-100).
Acquires ApoC-II + ApoE from HDL → mature VLDL.
Lipoprotein lipase degrades TAG (FA → adipose, glycerol → liver).
Hepatic lipase → IDL.
IDL loses ApoC-II/ApoE → LDL (main cholesterol transporter).
LDL taken up by LDL receptors on liver & extrahepatic tissues.

HDL & reverse cholesterol transport

Lipid-free ApoA-I (liver/intestine) gains phospholipid + cholesterol → disk-shaped nascent HDL → cholesterol esterified by LCAT → globular mature HDL.
Reverse cholesterol transport: HDL collects peripheral cholesterol (e.g. from macrophages) → LCAT esterifies → delivered to liver via SR-BI (or indirectly via VLDL remnant → LDL receptor) → bile acid synthesis/excretion (the only route to eliminate cholesterol). Protective against atherosclerosis.

Dyslipidemias — Classification

Dyslipidemia = disordered lipid metabolism: ↑plasma TAG and/or cholesterol, even when fasting.
Primary (~50%): genetic (mono-/polygenic), e.g. familial hypercholesterolemia.
Secondary (~40–50%): consequence of another metabolic disease (clarify the cause before treating).
Consequences: ↑cardiovascular risk, atherosclerosis, pancreatitis.

Fredrickson types (elevated lipoprotein)

Type I — chylomicron (familial hyperchylomicronemia; LPL or ApoC-II deficiency).
Type IIa — LDL (familial hypercholesterolemia).
Type IIb — LDL + VLDL (combined hyperlipidemia).
Type III — IDL/VLDL remnant (familial dysbetalipoproteinemia).
Type IV — VLDL (familial hypertriglyceridemia).
Type V — chylomicron + VLDL (mixed hypertriglyceridemia).

Primary Hyperlipoproteinemia Syndromes

Familial hyperchylomicronemia (Type I, AR)

Massive fasting hyperchylomicronemia → greatly ↑TAG; from LPL or ApoC-II deficiency. No ↑CV risk (LDL normal).
Symptoms: abdominal pain, pancreatitis, eruptive xanthomas, hepatosplenomegaly (young age).
Diagnosis: symptoms, ↑chylomicrons (“fridge test” → foam on top), LPL mutation analysis.
Treatment: low-fat diet.

Familial hypercholesterolemia (Type IIa, AD)

↑LDL + cholesterol, normal TAG; defective LDL-receptor synthesis/processing; greatly accelerated ischemic heart disease; LDL in macrophages → foam cells.
- Homozygotes: receptor-negative (0–2%) or receptor-deficient (2–25%); severe hypercholesterolemia from birth, xanthomas, CHD; statins ineffective (no LDL receptors) → low-cholesterol diet.
- Heterozygotes: most common AD disorder; hypercholesterolemia from birth, xanthomas, CHD; diet + statins (statins ↓endogenous synthesis → ↑LDL-receptor expression → better LDL clearance).

Familial dysbetalipoproteinemia (Type III, AD/AR)

Mutant ApoE → over-production/under-utilization of IDL; needs environmental cofactors (obesity, diabetes); ↑VLDL/chylomicron remnants, ↑TAG + cholesterol.
Symptoms: xanthomas (xanthoma striata palmaris), early atherosclerosis.
Diagnosis (adulthood): lab findings + ApoE mutation analysis. Treatment: diet + statin.

一問一答

▶What is the source, main lipid, and key apolipoprotein of VLDL?

Source: liver; main lipid: triglycerides; key apolipoprotein: ApoB-100 (plus C, E).

▶Which lipoprotein is the largest/lowest density, what does it carry, and where is it made?

Chylomicron — carries triglycerides, has ApoB-48 (plus A/C/E), and is made in the intestine.

▶What is the structural composition of a lipoprotein?

A hydrophobic core of cholesterol esters and triglycerides, surrounded by a hydrophilic surface of free cholesterol, phospholipids, and apolipoproteins.

▶What is the role of lipoprotein lipase in chylomicron metabolism?

On adipose/muscle capillaries it degrades triglycerides (fatty acids stored in adipose) and returns ApoC to HDL, producing the chylomicron remnant.

▶Which lipoprotein is the main blood cholesterol carrier, and from what is it derived?

LDL (ApoB-100), derived from IDL catabolism.

▶How is the chylomicron remnant cleared from the blood?

It is taken up by the liver via ApoE-mediated endocytosis.

▶Outline the VLDL → IDL → LDL endogenous transport pathway.

Liver secretes VLDL (TAG-rich, ApoB-100) → lipoprotein lipase degrades TAG → hepatic lipase forms IDL → IDL loses ApoC-II/ApoE to become LDL, the main cholesterol transporter.

▶Which enzyme esterifies cholesterol on HDL?

LCAT (lecithin-cholesterol acyltransferase), converting disk-shaped nascent HDL into globular mature HDL.

▶What is reverse cholesterol transport and why is it protective?

HDL collects peripheral cholesterol (e.g., from macrophages), LCAT esterifies it, and it is delivered to the liver via SR-BI for bile acid synthesis/excretion — the only route to eliminate cholesterol — making it protective against atherosclerosis.

▶What is the definition of dyslipidemia?

Disordered lipid metabolism with increased plasma triglycerides and/or cholesterol, present even in the fasting state.

▶What are the consequences of dyslipidemia?

Increased cardiovascular risk, atherosclerosis, and pancreatitis.

▶In the Fredrickson classification, what is elevated in Type I and what causes it?

Chylomicrons are elevated (familial hyperchylomicronemia), caused by LPL or ApoC-II deficiency.

▶What lipoproteins are elevated in Fredrickson Types IIa and IIb?

Type IIa = LDL (familial hypercholesterolemia); Type IIb = LDL + VLDL (combined hyperlipidemia).

▶What is elevated in Fredrickson Types III, IV, and V?

Type III = IDL/VLDL remnants (familial dysbetalipoproteinemia); Type IV = VLDL (familial hypertriglyceridemia); Type V = chylomicrons + VLDL (mixed hypertriglyceridemia).

▶Why does familial hyperchylomicronemia (Type I) NOT increase cardiovascular risk?

Because LDL is normal; the defect (LPL or ApoC-II deficiency) causes massive triglyceride/chylomicron elevation, presenting with pancreatitis, eruptive xanthomas, and hepatosplenomegaly rather than atherosclerosis.

▶What is the inheritance and molecular defect of familial hypercholesterolemia (Type IIa)?

Autosomal dominant; defective LDL-receptor synthesis/processing → ↑LDL and cholesterol with normal TAG, and greatly accelerated ischemic heart disease.

▶Why are statins ineffective in homozygous familial hypercholesterolemia?

Receptor-negative homozygotes have essentially no functional LDL receptors, so upregulating receptor expression cannot clear LDL; treatment relies on a low-cholesterol diet (and other measures).

▶How do statins work in heterozygous familial hypercholesterolemia?

Statins reduce endogenous cholesterol synthesis → increased LDL-receptor expression → better LDL clearance; used with diet.

▶What is the molecular basis of familial dysbetalipoproteinemia (Type III)?

A mutant ApoE causes over-production/under-utilization of IDL (↑VLDL/chylomicron remnants, ↑TAG and cholesterol); it needs environmental cofactors such as obesity or diabetes.

▶What proportion of dyslipidemias are primary versus secondary?

Primary (genetic, mono-/polygenic) ≈ 50%; secondary (consequence of another metabolic disease) ≈ 40–50%.