L17: Cholesterol Metabolism & Bile Acids

Question 1

LO1: Describe the structure of cholesterol

Answer 1

STEROL=steroid+alcohol

• lipid with four hydrocarbon rings (steroid) with hydrocarbon tail at one end and hydroxyl group at other end
• hydroxyl group forms hydrogen bonds with phospholipid/sphingolipid head groups

Question 2

LO2: Identify the primary substrate for cholesterol synthesis and 3 key intermediates

Answer 2

-primary substrate=acetyl CoA

1. HMG-CoA
2. Activated isoprenes (IPP and DPP)
3. Squalene (precursor for lanosterol)

Question 3

LO3: Identify the major regulated enzyme in the cholesterol biosynthetic pathway, its substrate and product, and the ways this enzyme is regulated

HMG~CoA + 2 NADPH → mevalonate + CoASH + 2 NADP+

Answer 3

HMG-CoA REDUCTASE

• substrate: acetoacetyl-CoA converted to…
• product: HMG CoA
• regulation: synthesis repressed by cytosolic cholesterol, peaks 6 hours after dark, minimum occurs 6 hours after light
  - activity increased by insulin+thyroid hormone, decreased by glucagon and cortisol
  - phosphorylation inactivates it, dephosphorylation activates it
  - inhibited by statin drugs

Question 4

LO4: List processes that influence cholesterol balance in tissues and describe the central role of the liver in maintaining cholesterol balance

Answer 4

1. Regulation of HMG CoA reductase/ synthesis of cholesterol
2. Release of VLDLs
3. Release of HDLs
4. Availability of chylomicrons
5. Glucagon/insulin ratio regulation
6. Conversion of cholesterol to bile salts
7. Regulation of plasma cholesterol levels via LDL uptake and HDL reverse transport

Liver=gatekeeper, collects all dietary cholesterol and synthesizes new cholesterol, packages cholesterol for transport to other tissues and for excretion

Question 5

LO5: Explain why a genetic deficiency of cell surface receptors for ApoB results in hypercholesterolemia

Answer 5

ApoB-100 interacts with LDL receptor to trigger endocytosis so that the LDL particple can be hydrolyzed for uptake

If deficient, LDL receptors are essentially defective, leading to hypercholesterolemia (chylomicrons remain in blood circulation instead of being taken up by peripheral tissues)

Question 6

LO6: Contrasts LCAT vs. ACAT in cholesterol metabolism

Answer 6

ACAT- Fatty acycl-CoA: Cholesterol Acyl Transferase

• involved in intracellular storage of cholesterol
• major tissues are the steroid synthesizing organs (adrenal glands, gonads, liver)
• fatty acyl donor= fatty acyl CoA

LCAT- Lecitin: Cholesterol Acyl Transferase

• involved in reverse transport of cholesterol
• associated with HDL particles
• substrate is the newly acquired HDL cholesterol, which is esterified and moved into center of HDL particle or transferred to VLDL remnant (LDL)
• fatty acyl donor=lecithin
• activated by ApoA1

Question 7

LO7: Explain the rationales for treating hypercholesterolemia with statins and cholestyramine

Answer 7

Statins inhibit HMG CoA reductase, reducing the rate of de novo cholesterol synthesis to reduce levels of cholesterol in the blood

Cholestyramine (binds bile salts so they’re not reabsorbed) increases the removal of bile acids from the body, causing body to convert more cholesterol to bile acids to compensate, and blood cholesterol levels subsequently decrease

Question 8

LO8: Identify the tissue(s) and subcellular localization where cholesterol is converted to bile acids

Answer 8

TISSUES

• liver (perivenous hepatocytes)
• secondary bile acids produced in intestine by bacterial enzymes

SUBCELLULAR LOCALIZATION
-some enzymes located in ER

Question 9

LO9: Name the enzyme that catalyzes the rate-limiting step in bile acid synthesis. What inhibits it?

Answer 9

Cholesterol-7/alph-hydroxylase

• hydroxylation of ring at B-6
• inhibited by cholic acid (negative feedback inhibition)

Question 10

LO10: Describe the difference in structure between bile acids and bile salts

Answer 10

BILE ACIDS

• amphipathic
• low pKa of side chain conjugated group

BILE SALTS

• bile acid+glycine or taurine via amide bond
• side chain of bile acid must be activated first by Coenzyme A
• increased emulsification power due to even lower pKa

Question 11

LO11: Describe the structural features that contribute to the ability of bile acids and bile salts to be good emulsifiers

Answer 11

amphipathic

low pKa of side chains

Question 12

LO12: Describe the enterohepatic circulation in bile acid metabolism

Answer 12

-circulation of biliary acids, bilirubin, drugs or other substances from liver to bile, followed by entry into small intestine, absorption by the eneterocyte, and transport back to the liver

• bile salts: primary method for cholesterol excretion, though reabsorption of bile acids/bile salts through enterohepatic circulation is very efficient (>95%)
• only lose about 0.5 grams of bile acids/day

1. Bile acids released into lumen of upper small intestine during digestion via CBD
2. Reabsorbed by lower small intestine into portal circulation (noncovalently bound to albumin for transport)