Molecular Fundamentals - Cholesterol Synthesis

cholesterol is synthesized where?

• primarily in liver

• secondary sites: intestine, adrenal cortex, ovaries, testes

overall, how many acetyl CoA are needed to produce cholesterol?

3

what enzymes combines 2 molecules of acetyl CoA to form aceto acetyl CoA?

thiolase

what enzyme adds another molecule of acetyl CoA to aceto acetyl CoA to form HMG-CoA?

HMG-CoA synthase

what is the rate limiting/committing step of cholesterol synthesis?

HMG-CoA reductase

HMG-CoA reductase converts HMG-CoA to what?

mevalonate

mevalonate goes through a series of steps to form what?

cholesterol

cholesterol is important for what?

membrane rigidity and membrane fluidity

cholesterol is precursor for what?

• steroid hormones (testosterone, progesterone, estrogen, corticosteriods)

• bile salts (important for emulsification of lipids)

statins inhibit what enzyme?

HMG-CoA reductase

if HMG-CoA reductase is inhibited, the body can’t do what?

synthesize cholesterol (have to get it from food)

what are adverse effects of statins?

• abdominal pain and nausea

• hepatotoxicity after the discontinuation of medication

By reducing how much cholesterol the liver makes, statins cause the liver to remove what?

more LDL ("bad") cholesterol from the blood, which helps lower levels and slow the formation of arterial plaque

statins also increase the number of LDL receptors in the liver, which helps do what?

remove cholesterol from the bloodstream

what are adverse effects of bile acids sequestrants?

constipation and bloating

what is the role of bile acid sequestrants?

binds to bile acids in the intestine, which prevents their reabsorption and forces the liver to use more cholesterol to make new bile acids

what are adverse effects of cholesterol absorption inhibitors?

allergic reactions

cholesterol absorption inhibitors should not be used in what population?

pregnant women or nursing mothers

ezetimibe will inhibit what?

micelle (cholesterol) receptors on enterocytes, not allowing intestinal absorption of dietary and biliary cholesterol

what are adverse effects of Niacin?

flushing, nausea, vomiting, diarrhea, dry skin

niacin inhibits what?

hormone-sensitive lipase (HSL) and prevents the hydrolysis of triglycerides, thereby reducing the release of free fatty acids from the adipocyte

PCSK9 normally does what?

degrades LDL receptors on liver

PCSK9 inhibitor will inhibit PCSK9 which will lead to what?

an increase in the number of LDL receptors on the surface of liver cells

lomitapide is an inhibitor of what?

MTP

lomitapide will inhibit the synthesis of what by inhibiting MTP?

chylomicron and VLDL

what are effects of lomitapide?

• fat accumulation in liver

• inhibition of fat absorption

• significant GI related adverse (nausea, dyspepsia, vomiting, and diarrhea)