Lipids Flashcards
What are lipoproteins?
Carriers of fats (hydrophobic core of TGs and cholesterol esters/hydrophilic outer portion w/ apoproteins embedded)
Transport TG /FAs for energy use and steroid synthesis, vitamin synthesis, etc
5 Classes of Lipoproteins (+ basics)
- Chylomicrons - most lipid/TG content; made in intestine to transport dietary/bile cholesterol; apo B 48 on surface
- VLDL - made in liver (apo B 100 on surface)
- IDL - from VLDL in plasma (can then go on to become LDL or bind apo E remnant receptor on liver if have apo E)
- LDL - from IDL in plasma
- HDL - smallest and highest density; about 50:50 lipid to protein content (least lipid/TG); made in intestine then collects cholesterol from tissues (chol acyl transferase). donates apoproteins E and C to others; delivers cholesterol back to liver
What are the functions of apoproteins B, C and E?
- Apo B- binds/recognizes LDL receptors on cells (B48 if from intestine and B100 if from liver)
- Apo C- activates LpL (lipoprotein lipase)
- Apo C-II activate LpL
- Apo C- III turns LpL off
- Apo E- binds/recognizes remnant receptors on liver (remnant recycling in liver)
- HDL donate apo CII and apo E to IDL and LDL
Lipoprotein Lipase
Degrades TGs –> FAs + glycerol (depletes chylomicrons, LDLs and IDLs of their TGs so these TGs can be delivered to given tissue
Once this process happens the lipoprotein is called a remnant
Familial Hypercholesterolemia
- Inherited defect in LDL receptor –> cannot get cholesterol into cell so high cholesterol levels in blood —> must rely on non-receptor mediated uptake of LDL into other tissues
- Leads to clinical findings - tendon xanthoma (fatty deposits on extensors like fingers, elbow, achilles) & corneal arcus (white streak in cornea - fatty deposit)
How do lipoproteins contribute to atherosclerosis?
1- Damage to intima —> more permeable and more adhesion so lipoproteins and monocytes can get into the sub-intimal area
2- Macrophages in sub-intimal area ingest oxidized LDL —> lipid accumulation —> fatty streak
3- Fatty streak grows into lipid core and fibrous cap of collagen/proteoglycans/activate smooth muscle form around the core (Sturdy cap = less chance of rupture)
4- Inflammation
* Accumulation of lipid core —> apoptosis AND macrophages full of cholesterol ester release cytokines —> inflammation/recruits cells —> WEAK CAP * Macrophages then secrete metalloproteases and collagenases which directly break down cap
5- Plaque Rupture
* If fibrous cap is broken down enough then lipid core is exposed to blood —> release tissue factor and PAI-1 —> hypercoaguable/thrombis formation
Statins (mechanism, pos effects, dosing)
- Mechanism - inhibt HMG-CoA reductase in liver —> inhibit cholesterol synthesis in liver (so less produced by liver) and —> inc expression of LDL receptors on liver (so more taken up by liver OUT of circulation)
- HMG-CoA reductase also involved in vascular pathways so statins have good vascular effects
- Anti-inflammatory
- Anti-thrombotic
- Antioxidant
- Statins also dec TGs and inc HDL
- Rule of 7 - inc dose 2x will only inc LDL reduction by 7%
What are the 2 most potent statins?
atorvostatin & rosuvastatin (50% reduction in LDL at max dose)
What 3 statins use CYP3A4?
drug:drug interactions for simvastatin, lovastatin & atorvastatin
Statin Side Effects
- Muscle aches (usually w/o CK elevation)
- R/o other causes of aches; check CK if symptomatic; if intolerable stop statin; if tolerable weigh pros and cons
- Try spacing out doses, dec dose, less intense statin, try other drugs/diet supplements
- Liver - extremely low risk; may see mild inc LFTs
- New onset DM - sometimes high dose statins inc glucose levels
- Cognitive - “foggy”
4 Statin Benefit Groups
1- Established ASCVD (secondary prevention)
2- LDL > or = 190 mg/dL
3- 40-75 yo w/ DM and LDL 70-189 mg/dL w/o ASCVD
4- 40-75 yp w/o DM and 10yr calc ASCVD risk > or = 7/5%
- Calculator based on… gender, age, race, total chol, HDL, HTN tx, DM, smoker, SBP
Ezetimibe
- Mechanism - blocks cholesterol absorption in intestine
- Mainly just dec LDL
- Depends on NPC1L1 protein
Bile Acid Sequestrants/Resins
- Mechanism - inhibit bile acid reabsorption —> dec bile in liver so makes more which requires cholesterol so inc LDL uptake by liver
- 20% reduction in LDL on own; good in conjunction w/ statin (better than statin + placebo)
- Lower LDL, raise HDL and raise TGs (caution in those w/ already high TGs)
- Main side effect is GI
Niacin (nicotinic acid)
- Mechanism - dec VLDL production in liver so less substrate for LDL in circulation (VLDL —> IDL —> LDL in circulation); also dec TG synthesis and inhibits lipase to dec free FA release
- Good b/c also inc HDL and reduces coronary events
- Side effects - flushing, headache, itching
- There is no additional benefit of adding Niacin to someone already on a statin
PCSK9 Inhibitors
- NEW
* Mechanism - monoclonal antibody against PCSK9 protein that normally prevents LDL receptor recycling in liver
