Lecture 24/25: Cholesterol, Lipoproteins Flashcards
Statins
Drugs that lower blood cholesterol
Cholesterol roles
Membrane fluidity, fat digestion (bile acids), steroid hormones; very hydrophobic w/ 4 ring structure
Familial Hypercholesterolemia (FH)
Major type: LDLR mutation. Elevated plasma cholesterol + LDL (accelerates atherosclerosis development), cholesterol deposits on tendons/arteries in homozyg.
Plasma lipoproteins
Particles that carry lipids at high concentration:
1. Chylomicrons
2. VLDLs
3. IDL
4. LDL
5. HDL
Larger = lower density cholesterol
Cholesterol sources
Synthesized primarily in liver cytoplasm + ER; also small part from diet
Committed step of cholesterol biosynthesis
HMG-CoA reductase -> irreversible reduction to mevalonate; rate-controlling, ER membrane anchored
Acyl-CoA Cholesterol Acyltransferase (ACAT)
Intracellular ER enzyme; esterifies cholesterol for storage/transport. Free cholesterol is found in membranes ONLY
Regulation of cholesterol biosynthesis via gene expression
- SREBP-SCAP proteins on ER membrane move to Golgi
- SREBP cleavage releases DNA binding domain
- DNA binding domain binds to Sterol Regulatory Elements (SREs) as transcrip. factor, upregulating gene expression
High cholesterol leads SCAP to bind membrane Insig, leading to ER retention
Hormonal regulation of HMG-CoA expression
Insulin, thyroxine in fed state signal high acetyl-CoA leading to upregulation
Glucagon, glucocorticoids downregulate HMG-CoA reductase
Statin regulation of HMG-CoA reductase
Statins are reversible, competitive inhibitors of HMG-CoA reductase, lowering cell. cholesterol synth. thus promoting cholesterol uptake from blood.
Cholesterol degradation
From liver:
1. Secreted into bile
2. Converted into bile acids
Plasma lipoprotein structure
Spherical shell comprised of phospholipids, free cholesterol, apolipoproteins
Core of TAGs/CEs; less dense = more TAGs
Chylomicrons
Signature Apo B-48 (also E, C-2)
Largest, least dense; deliver dietary TAGs to cells
Carry exogenous (dietary) lipids
Absorption of dietary fat
Digestion and solubilization of TAGs via pancreatic lipase + bile salts -> micelles for uptake
Lipoprotein lipase
Receptor on endothelial cells for cellular uptake of TAGs from chylomicrons; requires Apo C-2
Chylomicron interaction with HDLs
Collision of HDL/chylomicrons -> surface Apo exchange; chylomicron -> remnant
2 fates of Remnant plasma lipoproteins
- Apo E retained -> liver uptake via Remnant receptor
- Apo E loss to HDLs -> new nascent HDL disc
VLDL particles
Only produced in liver, contain endogenous (non-dietary) lipids.
Signature Apo B-100, also Apo C-2, E
Conversion of VLDLs to LDLs
VLDL TAG uptake via LPL -> IDL; loss of Apo E to HDLs -> LDLs
LDLs
High cholesterol:TAG ratio; only has Apo B-100.
LDL receptor pathway
- LDL binds LDLR localized to clathrin-coated pits
- LDL internalized within pit
- Endocytotic vesicles fuse with primary lysosomes
- Lysosomal lipases, esterases degrade TAGs, cholesteryl esters
- LDLRs recycled back to plasma membrane or degraded
Roles of free cholesterol leaving lysosome
- Suppress HMG-CoA reductase
- Increase ACAT
- Decrease surface LDLRs
HDL
Signature Apo A-1, comes from nascent HDL discs
Nascent HDL discs
Made directly from liver, intestine, chylomicron remnants.
Spherical HDL precursor; substrate for LCAT, req. Apo A1
HDL maturation
Disc picks up free cholesterol via LCAT (esterifies + packs) in plasma.
Free cholesterol from extrahepatic tissues (e.g. macrophages); ABCA1, SRB1, ABCG1 transfer cholesterol to HDL to be brought back to liver.
Can also exchange CE from HDL to other lipoproteins via CETP
Cholesteryl Ester Transfer Protein
Swaps CE for TG from HDLs to other lipoproteins; results in more CE in LDLs so more circulating cholesterol
Atherosclerosis pathogenesis
- Init. injury -> endothelial dysfunction
- LDL accumulates within intima and becomes oxidized
- Oxidized LDL triggers endothelial cytokine secretion, recruiting + activating macrophages
- Macrophages engulf ox. LDLs -> foam cells and recruit smooth muscle from media
- Further ox. LDL digestion -> creation of fatty streak, sm. muscle secretes fibers to form fibrous cap. Rupture can lead to a thrombus
HDL roles
- Promote LDL cholesterol efflux from macrophage (ABCA1)
- Promote oxidized LDL efflux from macrophages (ABCG1)
- Inhib LDL oxid.
- Inhib vascular inflammation, promote endothelial repair
Cholestyramine
Bile salt sequestrant, increases bile salt excretion/inhibs reabsorption resulting in increased cholesterol consumption to lower serum cholesterol (upreg. LDLR, HMG CoA reduct.)
How do oats reduce cholesterol?
Thickening of digested food results in less cholesterol uptake. Also binds + sequesters bile acids.
PCSK9 inhibitor
Works with statins to further increase LDLR upregulation due to low cellular cholesterol, further promoting uptake of cholesterol from blood. Blocks LDLR protease, promoting recycling.
Effect of decreased intestinal cholesterol uptake
- Decreased CE in chylomicrons
- Decreased CE return to liver via remnant
- Decreased hepatic cholesterol stores
- Decreased VLDL production
- Increased LDLRs -> decreased circulating LDL
