L38, L39: Abnormal Lipid Metabolism, Atherosclerosis, Science of Cholesterol and Lipids Flashcards
Exogenous pathway of lipid metabolism (dietary lipid)
- Enterocyte secrete chylomicron rich in TAG (TAG, Apo B48)
- Apo C2 + Apo E transferred to chylomicron from HDL (TAG, Apo B48, Apo C2, Apo E)
- Lipoprotein lipase activated by Apo C2 degrade TAG —> FA + glycerol
- Apo C2 return to HDL
- Chylomicron remnant (CE, Apo B48, Apo E) bind to liver through Apo E and endocytosed
- Metabolised by liver —> Bile acids + Cholesterol —> back to intestine
Endogenous pathway of lipid metabolism (endogenously synthesised lipid)
- Liver secrete VLDL rich in TAG (TAG, Apo B100)
- Apo C2, Apo E transferred to VLDL from HDL (TAG, Apo B100, Apo C2, Apo E)
- Lipoprotein lipase activated by Apo C2 degrade TAG —> FA + glycerol
- Apo C2 return to HDL (VLDL —> IDL: CE, Apo B100, Apo E)
- IDL bind to HDL and return Apo E (IDL —> LDL: CE, Apo B100) or IDL bind to liver via Apo E —> endocytosed
- LDL (CE, Apo B100) bind to extrahepatic tissue and liver —> endocytosed
Function of HDL
- Take up excess cholesterol from body cells and transfer to VLDL, IDL, LDL so that they can be taken up by liver
- LCAT: cholesterol —> CE —> Mature HDL
- Mature HDL (with Apo A1) transfer CE to VLDL, IDL, LDL in exchange for TAG (via CETP)
- Mature HDL (with Apo A1) taken up by liver and steroid hormone producing tissue
***Chylomicron, Chylomicron remnant, VLDL, IDL, LDL, HDL composition
Chylomicron: TAG + Apo B48 Chylomicron remnant: CE + Apo B48 + Apo E VLDL: TAG + Apo B100 IDL: CE + Apo E + Apo B100 LDL: CE + Apo B100 HDL: TAG + Apo A1
Apolipoprotein function
***Apo C2: activate lipoprotein lipase
Apo A1, A2: LCAT activator
Apo B48: secretion of chylomicron / VLDL
***Apo B100: LDL receptor binding (bind to extrahepatic tissue / liver)
***Apo E: IDL (bind to HDL) and chylomicron remnant (bind to liver) receptor binding
Tests to distinguish lipid composition of blood
- Phenotypic observation of blood —> standing plasma test
2. Lipoprotein electrophoresis —> Fredrickson Classification
Fredrickson Classification
- Type I: defective Apo C2
—> ↑ chylomicron
—> Chylomicronaemia - Type IIa: deficient LDL receptor
—> ↑ LDL
—> familial hypercholesterolaemia - Type IIb: deficient LDL receptor + defective Apo B100
—> ↑ VLDL, ↑ IDL, ↑ LDL
—> familial hypercholesterolaemia - Type III: deficient Apo E
—> ↑ IDL, ↑ chylomicron remnant
—> dys-beta-lipoproteineamia - Type IV: unknown
—> ↑ VLDL
—> sporadic hypertriglyceridemia - Type V: low lipoproteinlipase
—> ↑ chylomicron, ↑ VLDL
—> sporadic hypertriglyceridemia
LDL-cholesterol, TAG in association with coronary artery disease
- LDL-cholesterol: atherosclerosis
- small
- CE rich
- Apo B100
- LDL receptor regulated by PCSK9
- high LDL —> oversupply of CE to cells —> inhibit LDL receptor + HMG-CoA reductase synthesis
- high LDL infiltrate activated endothelium by diffusion —> atheroma —> lesion of fibrous plaque (lipid, SMC, macrophage, CT) —> Thrombosis
- Activated endothelium
—> ↑permeability
—> ↑leukocyte adhesion
—> ↑inflammatory cytokine
—> ↓vasodilator molecules
—> ↓anti-thrombotic molecules
- Activated SMC
—> ↑inflammatory cytokine
—> ↑ECM synthesis
—> ↑migration into intima and proliferation - Elevated TAG: insulin resistance
Dietary lipid metabolism
From diet to enterocytes
- Cholesterol (90%) uptake by enterocyte (***uptake via NPC1L1 receptor by clathrin-mediated endocytosis)
- CE (10%) —> Cholesterol (by cholesterol esterase)
- Phosphatidylcholine (phospholipid) —> glycerylphosphorylcholine (lipase)
- TAG —> 2-monoacylglycerol (pancreatic lipase)
Within enterocytes
1. Cholesterol —> CE (ACAT2: add fatty acyl chain to cholesterol)
2. 2-monoacylglycerol —> TAG (re-esterification: add fatty acyl chain)
3. amino acids —> Apo B48
4. Phospholipids
—> ALL packaged in chylomicron
Absorption of cholesterol
- Cholesterol (90%) uptake by enterocyte (***uptake via NPC1L1 receptor by clathrin-mediated endocytosis)
- CE (10%) converted to cholesterol first by cholesterol esterase
Within enterocytes
- Cholesterol —> CE (ACAT2: add fatty acyl chain to cholesterol)
- CE packaged with Apo B48, TAG, phospholipid into chylomicron by MTP (microsomal triglyceride transfer protein)
Causes of increased cholesterol in body
- ↑ absorption of cholesterol into intestinal
- age-related increase in NPC1L1 receptor
- inhibition of NPC1L1 by Ezetimibe - ↓ excretion of bile acids
- age-related decrease in BSH+ species (bile acid hydrolase) e.g. Lactobacillus
- decline in bacterial modification of bile acid —> ↓ secondary bile acid —> reduced excretion of bile acids —> reduced cholesterol utilisation to produce replacement bile acids
- supplementation with Probiotics - ↓ synthesis of bile acids by liver
- decline in CYP7A1 expression —> ↑ cholesterol - ↓ LDL-cholesterol clearance from bloodstream to hepatocyte
- age-related + ↓cholesterol demand for bile acid synthesis —> ↓LDL receptor
- ↑ LDL-C residence, ↓ LDL-C clearance
Excretion: 2 mechanisms to remove cholesterol from liver
- Direct efflux to gallbladder
- Converted to bile acid —> efflux to gallbladder
—> in gallbladder —> release into small intestine postprandially in response to Cholecystokinin
Synthesis of cholesterol by HMG-CoA reductase
- 3x acetyl-CoA —> HMG CoA (HMG CoA synthase)
- HMG CoA —> mevalonic acid (rate-limiting: HMG CoA reductase)
- Mevalonic acid —> activated Isoprene units (require ATP)
- 6x Isoprene units —> Squalene
- Squalene —> Cholesterol (cyclisation)
Control of level of HMG CoA reductase in body
- Regulation of gene expression (Sterol-dependent)
- insulin and thyroxine upregulate expression for HMG CoA reductase
- glucagon and glucocorticoid downregulate expression for HMG CoA reductase - Enzyme degradation (Sterol-accelerated)
- Phosphorylation / dephosphorylation (Sterol-independent)
- dephosphorylated —> active HMG CoA reductase - Control by drugs (HMG CoA reductase inhibitor)
Biochemical pathogenesis of familial hypercholesterolaemia
- **- Autosomal Dominant
- LDL-receptor gene deficiencies
- PCSK9 gene deficiencies
- Apo B gene deficiencies
- heterozygous —> inadequate LDL-R on hepatocyte —> Xanthomas, arcus cornealis
- homozygous —> minimal LDL-R on hepatocyte —> Xanthomas in early childhood
