2s: Lipoproteins Flashcards
Atherosclerotic plaque structure
necrotic core (dead macrophages) of cholesterol crystals
surrounded by foam cells (macrophages) topped with a fibrous cap
Cholesterol and triglyceride levels in plasma lipoproteins
Cholesterol triglycerides
- Cholesterol enters intestines and is solubilised into mixed micelles
- The cholesterol is transported across the intestinal epithelium by NPC1L1 (main determinant of transport)
- Two transporters can transport cholesterol back into the lumen of the intestines – a balance between these transporters determines the net amount of cholesterol absorbed)
- ABC G5
- ABC G8
- Bile acids are reabsorbed in the terminal ileum
- Cholesterol downregulates the activity of HMG CoA reductase (the main enzyme to create cholesterol from acetate and mevalonic acid) at the liver – i.e. the amount of cholesterol synthesised in the liver is dependent on the amount of cholesterol absorbed in the small intestines
- The fates of cholesterol brought to the liver (produced IN the liver or absorbed and transported):
- Hydroxylation by CYP7A1 enzyme, 7a-hydroxylase→ bile acids → excreted via bile ducts
- Esterified by ACAT → cholesterol esters and combined with TG and apoB into VLDL (precursor to LDL)
- ACAT = Acyl-CoA: cholesterol acyltransferase
- MTP = Microsomal Triglyceride Transfer Protein (used to package cholesterol esters)
- After circulation, LDLs will bind to LDL receptor on the liver
- HDLs are responsible for picking up excess cholesterol from the periphery. There is an important transporter called ABC A1 which is important in packaging free cholesterol from the periphery into HDLs
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CETP (cholesteryl ester transfer protein) mediates the movement of:
- Cholesterol from HDL to VLDL
- Triglyceride from VLDL to HDL
Some of the HDLs will be taken up by the liver via a receptor called SR-B1
Give 4 types of primary hypercholesterolaemia
Familial hypercholesterolaemia (FH) = AD (or rarely, AR) mutation LDL-R, apoB or PCSK9
Polygenic hypercholesterolaemia = NPC1L1, HMG-CoA Reductase, CYP7A1 polymorphisms
Familial hyper-a-lipoporteinaemia = CETP deficiency
Phytosterolaemia = ABC G5 and G8 mutations → premature atherosclerosis
Clinical presentation of hypercholesterolaemia
LDL binds to LDL-R and undergoes endocytosis → many LDL-R mutations identified
homozygotes = corneal arcus, xanthomas (eye [xanthelasma], tendon)
Clinical presentation of hypercholesterolaemia
LDL binds to LDL-R and undergoes endocytosis → many LDL-R mutations identified
homozygotes = corneal arcus, xanthomas (eye [xanthelasma], tendon)
PCSK9 function and mutation consequence
Function = bind to LDL-R and aid LDL-R degradation
[RARE] FH from AD-inherited gain-mutation in PCSK9 → increased LDL-R degradation
- loss of function mutations of PCSK9 are associated with low LDL levels
3 types of Hypertriglyceridaemia (primary)
Familial T1 = lipoprotein lipase / apoC II deficiency
- less breakdown of chylomicrons
- some xanthomas
Familial T4 = increased synthesis of TG (unknown cause)
- Majority VLDLs
Familial T5 = apoA deficiency
- Majority VLDLs (with some chylomicrons)
3 types of mixed hyperlipidaemia (primary)
Familial combined hyperlipidaemia (unknown cause)
Familial hepatic lipase deficiency
Familial dys-b-lipoproteinaemia (type III hyperlipoproteinemia)
- ApoE2 polymorphism (ApoE4 = increase Alzheimer’s, ApoE2 = less Alzheimer’s; ApoE3 = normal)
- Diagnostic sign = Yellow palmar crease (LEFT), xanthomas on elbow (MIDDLE)
- Secondary hyperlipidaemia (non-genetic cause) → e.g. PBC (image on RIGHT)
4 types of hypolipidaemia
- Aβ-lipoproteinaemia: MTP deficiency (AR) – RARE
- Hypoβ-lipoproteinaemia: truncated apoB (AD)
- Tangier disease: orange tonsils, HDL deficiency caused by ABC A1 mutations
- Hypoα-lipoproteinaemia (apoA-I mutations)
Pathology of atherosclerosis
Examples of lipid-regulating drugs
Lp(a) lipoprotein A
CVD risk factor marker
- Should be measured once with intermediate-high CVD/CHD risk (inc. FH)
- Desirable Lp(a) = <500mg/L
- Tx is nicotinic acid 1-3g/day
Obesity mx
Treatment
Benefits/risks of surgery
Treatment
- low-calorie diet and exercise
- iatrogenic malabospriton (Orlistat, 120 - 360 mg, OD)
- Bariatric surgery (BMI >40kg/m2) e.g. gastric banding, bypass biliopancreatic bypass
Benefits/risks of surgery
- success → 50% loss in weight, 72% reduction of diabetes risk, reduced TG, increased HDL, reduced fatty liver, reduced HTN
- post-op mortality = 0.1-2%
Biliopancreatic diversion > gastric bypass > medical therapy
Management of hyperlipidaemia
