Hyperlipidemia Flashcards
Describe exogenous lipid transport
- cholesterols/TGs emulsified in intestines by bile acids then form chylomicrons (apo B48!) in gut wall
- enter circulation and use LPL to deliver TGs to adipose and muscle tissue
- remaining chylomicron remnant brings cholesterol to liver
Describe endogenous lipid transport
A) liver forms VLDL, releases in circulation
- TGs delivered to adipose
- VLDL converted to IDL and LDL
- LDL takes cholesterol to tissues to incorporate into cell membranes/steroids
B) LDL can also take cholesterol and bring to atheromas in arterial walls
- LDL is oxidized and phagocytosed by macrophages to become foam cells
C) LDL can also bring cholesterol to liver, which promotes endocytosis of LDL receptors
What are the three intracellular regulatory effects of cholesterol on the hepatocyte?
1) decreases activity of HMG CoA reductase
2) activates ACAT, which esterifies free cholesterol into cholesterol ester for storage
3) inhibits transcription of gene encoding LDL-R
Describe reverse cholesterol transport
- HDL particles secreted by gut and liver, utilize plasma LCAT to take cholesterol from tissues and atheromas
- HDL brings cholesterol back to liver
1) OUCH my endothelium got injured! Damn hypertension
2) here comes the LDL, and it oxidizes
3) blood monocytes stick and become macrophages
4) macrophages eat the LDL, become foam cells
5) platelets adhere
6) smooth muscle cell migrates and throws down collagen
What was just described?!
- fibrous plaque formation, the typical advanced lesion of atherosclerosis
- complications include necrosis and lysis of plaque
Name some secondary causes of hyperlipidemia
- hypothyroidism
- early nephrosis
- cholestasis
- hypopituitarism
- corticosteroid excess
What are the major risk factors for hyperlipidemia?
- serum LDL cholesterol
- age
- hypertension
- smoking
What are the three “anti-atherogenic” explanations for why HDL is the bee’s knees?
1) role in reverse cholesterol transport
2) protects against endothelial dysfunction
3) inhibits oxidative stress
If you had to describe someone that had naturally hearty HDL concentrations, what would you say?
- premenopausal (estrogens!) lean woman that works out a lot, enjoys a glass of wine with dinner, and has a family history of hyperalphaproteinemia
If you had to describe someone that had pretty poor levels of HDL, what would you say?
- post pubescent fat man that smokes, has type II diabetes, and has a family history of HDL deficiency
A patient is started on a drug for their hyperlipidemia. After use, their HDL is increased while TG and LDL is decreased. Things are going great, but the patient starts noticing some redness and itching of his face. This is tolerable, but when running a normal blood panel you notice his LFTs are elevated. What drug was started and how does it work?
- Niacin
- decreases triglyceride synthesis in the liver
- decreases lipolysis in adiposes tissue, which reduces transport of FFA to liver
- reduces hepatic clearance of HDL apo A1, which raises HDL levels
If a patient is severely hypertriglyceridemic, what is a group drug choice for them, how does it work, and what are some adverse effects?
- Fibrates
- bind to PPARa, increase expression of LPLs, and inhibit apoCIII expression
SE: gallstones, myositis
If I want to nip the absorption of bile salts in the bud, right at the level of the gut, what are drugs I can use?
- bile acid sequestrants (cholestyramine, colestipol) - reduce LDL but slight increase in TG/HDL
- ezetimibe - inhibits transport protein in jejunum, used as complement to statins
How do statins work?
- reversible, competitive inhibitors of HMG-CoA reductase
- also increases synthesis of LDL receptors and causes reduction in hepatic VLDL
Name the statins we learned about and their major side effects
- mevastatin, locastatin, simvastatin, pravastatin, atorvastatin, fluvastatin, rosuvastatin
- SE: hepatic dysfunction, myopathy/rhabdomyolysis
