Anti-hyperlipidemic drugs Flashcards by Brooke Thornburg

Importance of cholesterol metabolism to public health

-Brown and Goldstein
-cholesterol metabolism
-59% decline in death rate from CHD from 1950-1999

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Major lipids

-cholesterol
-triglyceride

-transported in blood as lipoproteins bc very hydrophobic

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Cholesterol

-essential component of cell membranes
-precursor to sterols and steroids
-STRUCTURE

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Triglyceride (triacylglycerol)

-storage form of fuel to support generation of high energy compounds
-component of structural lipids
-STRUCTURE

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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

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Lipoprotein lipase systems

-release free fatty acids from lipoproteins

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Lipoprotein structure

-apoprotein on surface (regulation)
-surface: phopholipid, protein, and cholesterol
-core: tg and cholesterol esters

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Classes of lipoproteins (largest to smallest)

-Chylomicrons
-VLDL
-IDL
-LDL
-HDL

-based on density, composition and electrophoretic mobility

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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

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VLDL

-very-low
-secreted by liver into blood as source of tgs
-mostly tgs

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IDL

-intermediate
-tg-depleted VLDLs

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LDL

-low
-main cholesterol form in blood
-mostly cholesterol

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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

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Centrifugation

-HDL densest at bottom with ApoA1
-VLDL and chylomicron remnants at top with ApoB

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important apoliproteins

-ApoA-I
-ApoB-100
-ApoE
-ApoCII

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ApoA-I

-structural in HDL
-ligand of ABCA1 receptor
-mediates reverse cholesterol transport! (also how HDLs are formed)
-produced in liver and intestine

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ApoB-100

-structural in VLDL, IDL, LDL
-LDL receptor ligand
-produced in liver

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ApoB-48

-structural in chylomicrons
-production of chylomicrons and transport reminants to liver
-produced in intestine!

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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

1. acetoacetyl CoA + acetyl CoA -HMG-CoA synthase 2. hydroxymethylglutaryl-CoA -HMG-CoA reductase + 2 NADPH 3. Mevalonate 4. IPP + DMAPP 5. GPP + IPP 6. FPP + squalene 7. Lanosterol -19steps 8. 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

1. fatty streak 2. 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

1. esterification by ACAT1 2. 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