Hyperlipidemia Flashcards
Lipoprotein Structure
Lipid rich core (triacylglycerols and cholesterol esters)
Phospholipid monolayer
Apolipoproteins and cholesterol embedded in the membrane
Chlylomicrons and VLDL
Largest circulating lipoproteins
Produced in the intestine from dietary lipids emulsified by bile acids
High TAG content
Low cholesterol content
Low protein content but high complexity of proteins
LDL
Medium size lipoproteins
Low TAG content
50% cholesterol (most of the circulating cholesterol - primary means of transport to peripheral tissues)
Higher protein content but less complex
HDL
Smallest circulating lipoproteins Low TAG content Medium amount of cholesterol High protein content and complex array Mature by acquiring lipid from VLDL and chylomicrons, and/or acquiring cholesterol from peripheral tissues
2 ways body gets rid of excess cholesterol
- conversion of cholesterol into bile acids
2. secrete excess into the bile
Lipoprotein Lipase
Present on the surface of most tissue capillaries
Releases FAs from TAGs (lipoprotein lipase mediated lipolysis)
Chylomicron remnant taken up by the liver (RM endocytosis)
Reverse Cholesterol Transport
HDL can transport cholesterol back to the liver via scavenger receptor BI mediated uptake.
Can be excreted from body directly in bile or after conversion to bile acids
Therapeutic Lifestyle Changes
Diet: reduce intake of cholesterol and saturated fats, increase intake of fiber and plant sterols
Excercise
Smoking cessation, reduce alcohol
Reduce hypertension, obesity, hyperglycemia
Statins
First choice for patients with high LDL
Competitive inhibitors of HMG CoA reductase (reduce liver chol biosyn and deplete intracellular chol stores)
Primary action: Increase hepatocyte LDL receptor levels (indirect effect is inhibiting chol biosyn)
Anti-inflammatory, anti-coagulant
Limited benefit for Type IIa with LDL receptor mutations
Safe and well tolerated
Adverse: reversible liver toxicity, cardiomyopathy, drug interactions
Niacin
Reduces circulating LDL and cholesterol levels
Inhibits lipolysis in adipose tissue = reduced circulating FAs/FA biosyn/VLDL syn and secretion/serum LDL
May moderately increase serum HDL
Effective in combo - not usually on own
Limited by high doses needed and adverse effects (flushing, hot flashes, GIT irritation, hepatotoxicity)
Bile Acid Binding Resins
Anion exchange resin that binds bile acids in the small intestine
Complex is excreted in feces (reduces bile acid reabsorption so need to break down chol to make more - accelerate rate of bile acid syn in the liver)
Increased expression of LDL receptors to lower LDL levels
Safe and relatively effective
Do not interfere with absorption of dietary lipids and lipid soluble vitamins
Take with statins to reduce compensatory increase in chol synthesis
Cholesterol Absorption Inhibitors
Inhibit cholesterol absorption from the small intestine (dietary or endogenous (secreted in bile))
Deplete hepatic cholesterol (increase LDL receptor expression and reduce serum total cholesterol and LDL)
Used in combo with other drugs
Fibrates
First choice to treat high serum TAGs and/or reduce HDL
PPARalpha agonists
Anti-atherosclerosis effects (increase chylomicron and VLDL clearance, promote reverse chol transport, anti inflammatory)
Well tolerated (some GI irritation, liver toxicity, rash, cardiomyopathy)
PPARalpha
A ligand activated transcription factor that increases the expression of genes involved in lipid metabolism
What does PPARa cause an increase in the expression of?
- Endothelial lipoprotein lipase (accelerates clearance of TAG rich chylomicrons and VLDL from serum)
- Hepatic FA oxidation enzymes (reduces TAG and VLDL synthesis)
- Hepatic apo A-I and A-II (increases HDL synthesis)
