Anti-hyperlipidemic drugs Flashcards
Importance of cholesterol metabolism to public health
-Brown and Goldstein
-cholesterol metabolism
-59% decline in death rate from CHD from 1950-1999
Major lipids
-cholesterol
-triglyceride
-transported in blood as lipoproteins bc very hydrophobic
Cholesterol
-essential component of cell membranes
-precursor to sterols and steroids
-STRUCTURE
Triglyceride (triacylglycerol)
-storage form of fuel to support generation of high energy compounds
-component of structural lipids
-STRUCTURE
Lipoprotein
-transport cholesterol and tgs in blood
-spherical particles w phospholipid, free cholesterol and protein making up surface
-core made of tg and cholesterol ester
-apoproteins on surface critical in regulating transport and metabolism
-lipoprotein lipase system
Lipoprotein lipase systems
-release free fatty acids from lipoproteins
Lipoprotein structure
-apoprotein on surface (regulation)
-surface: phopholipid, protein, and cholesterol
-core: tg and cholesterol esters
Classes of lipoproteins (largest to smallest)
-Chylomicrons
-VLDL
-IDL
-LDL
-HDL
-based on density, composition and electrophoretic mobility
Chylomicrons
-transport dietary lipids from gut to liver and adipose tissue
-formed in intestine
-too big to absorb into capillaries, enter lymph node
-mostly tg structure
VLDL
-very-low
-secreted by liver into blood as source of tgs
-mostly tgs
IDL
-intermediate
-tg-depleted VLDLs
LDL
-low
-main cholesterol form in blood
-mostly cholesterol
HDL
-high
-secreted by liver and acquire cholesterol from peripheral tissues and atheromas (reverse cholesterol transport)
-bring cholesterol from tissue back into liver
-ApoA-I
Centrifugation
-HDL densest at bottom with ApoA1
-VLDL and chylomicron remnants at top with ApoB
important apoliproteins
-ApoA-I
-ApoB-100
-ApoE
-ApoCII
ApoA-I
-structural in HDL
-ligand of ABCA1 receptor
-mediates reverse cholesterol transport! (also how HDLs are formed)
-produced in liver and intestine
ApoB-100
-structural in VLDL, IDL, LDL
-LDL receptor ligand
-produced in liver
ApoB-48
-structural in chylomicrons
-production of chylomicrons and transport reminants to liver
-produced in intestine!
ApoE
-ligand for LDL remnant receptor
-reverse cholesterol transport w HDL!
-produced in liver and other tissues
ApoCII
-chylomicrons and VLDL
-binds to llipoprotein lipase to enhance tg hydrolysis to fatty acids
Lipid absorption and transport
-exogenous path (intestine)
-endogenous path (liver)
Exogenous pathway
-dietary fat and cholesterol absorbed in intestine
-packaged into chylomicrons by bile acids from liver
-LPL breaks down tgs of chylomicron to FFAs that go to adipose tissue or peripheral tissue
-free FFAs from liver go to adipose tissue
-chylomicron reminants go to remnant receptors with help of LPL, HL, APOE
Endogenous pathway of lipid transport
-VLDL from liver to IDL and FFA by LPL
-FFA go to adipose or peripheral tissues
-IDL either goes back to liver w ApoE help or turns into LDL by LPL and HL
-LDL either goes to peripheral tissues to distribute cholesterol or back to liver (LDL receptors) ApoB mediated
Lipoprotein lipase (LPL) found in
-capillaries of fat
-cardiac and skeletal muscle
Hepatic lipase (HL) found in
-produced in liver
-convert IDL to LDL!!
Atherosclerotic plaque from endogenous pathway
-LDL oxidized
-scavenger receptors on macrophages
-turn into foam cells
oh boy
slide 13
HDL formation
-ApoA1 takes cholesterol from tissues to make HDL
-HDL to IDL by LCAT and CETP
-or HDL to liver, steroid-secreting cells
LCAT
-lethicin-cholesterol acyltransferase
-on LDL and HDL
-HDL to IDL
CETP
cholesterol ester transfer protein in blood
-HDL to IDL
Cholesterol synthesis
-liver most critical to total body burden
-de novo is major source
-acetoacetyl CoA + acetylCoA to cholesterol
Cholesterol synthesis steps
- acetoacetyl CoA + acetyl CoA
-HMG-CoA synthase - hydroxymethylglutaryl-CoA
-HMG-CoA reductase + 2 NADPH - Mevalonate
- IPP + DMAPP
- GPP + IPP
- FPP + squalene
- Lanosterol
-19steps - cholesterol
-IPP=isopentenyl pyrophosphate
-DMAP=dimethylallyl pyrophophate
-GPP=geranyl
-FPP= farnesyl
Diseases from lipoprotein disorders
-hyperlipoproteinemia
-hypertriglyceridemia
Hyperlipoproteinemia
-artherosclerosis (accumulation of cholesterol in vascular smooth muscle)
-premature CAD
-stroke
Hypertriglyceridemia
-pancreatitis
-xanthomas
-inc risk of CHD
Deadly duo
-artherosclerotic plaque + thrombosis
-plaque rupture
Artherosclerosis patho
- fatty streak
- accumulated plaques
-oxidation +/- endothelial damage (sheer stress)
LDL oxidation in artherosclerosis
-cigarette smoking
-taken up by macrophages
-oxidized LDLs activates T cells to convert monocytes to macrophages via cytokines also inc chemotaxis into intima
-T cells stimulate proliferation of smooth muscle cells = hypertrophy = smooth muscle cells move into intima
-all leads to accumulation of LDL, macrophages, and smooth muscles
-
Sheer stress
-flow of blood damaging endothelium
-HTN inc risk of artherosclerosis bc more sheer stress
Damage of endothelium in artherosclerosis
-damage causes monocytes to flow in
-upregulation of adhesion molecules that let monocytes from outside stick to endothelium and enter intima where they turn into macrophages
Accumulation of LDL, macrophages, smooth muscle in intima (Artherosclerosis)
-macrophages and smooth muscle take up LDL cholesterol
-take up so much and covert to cholesterol ester = foam cells
-foam cells die and deposit cholesterol ester in blood vessel
Subendothelial uptake of cholesterol by macrophages
-initiated by LDL accumulation
-influx and efflux pathway
-2 fates
influx pathway of cholesterol uptake by macrophage
–influx and efflux pathway
-LDL enter macrophage by pinocytosis or LDLR
-mLDL enters by SR-A or CD36
-both to lysosome
efflux pathway of cholesterol uptake by macrophage
- esterification by ACAT1
- back to free cholesterol by CEH and freed by ApoA1 and HDL
-Apo1 binds ABCA1 to free cholesterol
-SR-BI = HDl +FC
-HDL binds ABCG1 to free cholesterol
ACAT1
-acylCoA cholesterol acyltransferase
-esterifies cholesterol in macrophage
-tried to inhibit this but didnt work that well
CEH
-cholesterol ester hydrolase
-de-esterifies cholesterol in macrophage
