Lipid metabolism

Lipoproteins

Lipoprotein	Main lipid	Apo	Role
Chylomicron	Dietary TG	B48	Gut -> tissues
VLDL	Endogenous TG	B100	Liver -> tissues
IDL	TG + cholesterol	B100	VLDL remnant
LDL	Cholesterol	B100	Delivers cholesterol; atherogenic
HDL	Cholesterol	A1	Reverse cholesterol transport
Lp(a)	Cholesterol	apo(a) + B100	Genetically fixed; atherogenic + prothrombotic

Heterozygous familial hypercholesterolaemia ~1 in 250 - the commonest serious monogenic disorder, and largely undiagnosed
Elevated Lp(a) in ~20% of the population
Secondary dyslipidaemia is far commoner than primary

Dietary fat -> chylomicrons (apoB48)
- -> lipoprotein lipase at capillary endothelium releases free fatty acids
- -> chylomicron remnants cleared by the hepatic remnant receptor

Liver secretes VLDL (apoB100)
- -> LPL -> IDL
- -> hepatic lipase -> LDL
- -> LDL cleared by the hepatic LDL receptor binding apoB100

HDL accepts peripheral cholesterol via ABCA1
- -> LCAT esterifies it
- -> delivered to liver via SR-B1, or transferred to apoB lipoproteins by CETP

LDL receptor mutation (familial hypercholesterolaemia)
- -> dec hepatic LDL clearance -> inc LDL-C
- -> excess LDL taken up by macrophage scavenger receptors - unregulated, no feedback
- -> foam cells -> atheroma
Same phenotype from apoB100 mutation or PCSK9 gain-of-function
LPL or apoC-II deficiency -> chylomicronaemia -> pancreatitis

Fasting not required for routine lipids
- Except when triglycerides are very high or chylomicronaemia is suspected
Non-HDL-C and apoB capture atherogenic particle burden better than LDL-C when TG is raised
Measure Lp(a) once in a lifetime - genetically determined, not diet- or statin-responsive
Familial hypercholesterolaemia: Dutch Lipid Clinic Network criteria
- LDL-C level, tendon xanthomata, premature CVD, family history
- Genetic testing confirms and enables cascade screening

Lipid-lowering itself is covered in lipid-modifying agents
LDL lowering is the intervention with the causal evidence
Each 1.0 mmol/L LDL-C reduction:
- ~10% dec all-cause mortality
- ~20% dec coronary death
- ~23% dec major coronary events
- ~17% dec stroke
Severe hypertriglyceridaemia -> fibrate, alcohol abstinence, glycaemic control, low-fat diet
Treating secondary causes often normalises the profile without a lipid drug

Raise LDL

Raise triglycerides

Lower HDL

Special case

Cholestatic liver disease (e.g. PBC) - lipoprotein-X accumulation
- Raised LDL with markedly raised HDL
- Cardiovascular risk is generally not increased despite the alarming profile

LDL exposure is cumulative - the relevant unit is mmol/L x years, not the current value
Untreated heterozygous FH: coronary disease from the 4th-5th decade
Homozygous FH: coronary disease in childhood
Elevated Lp(a) -> independent risk for ASCVD and for calcific aortic stenosis
Severe hypertriglyceridaemia -> acute pancreatitis, eruptive xanthomata, lipaemia retinalis

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