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Questions and Answers
Which structural component is NOT part of cholesterol?
Which structural component is NOT part of cholesterol?
What is a precursor to bile acids?
What is a precursor to bile acids?
Which of the following best describes the regulation of HMG-CoA reductase?
Which of the following best describes the regulation of HMG-CoA reductase?
Which process describes the reversible circulation of bile acids in the body?
Which process describes the reversible circulation of bile acids in the body?
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Which statement is true about cholesterol metabolism?
Which statement is true about cholesterol metabolism?
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Where is most of the cholesterol in cellular membranes found?
Where is most of the cholesterol in cellular membranes found?
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What is a significant consequence of the imbalance in cholesterol influx and efflux?
What is a significant consequence of the imbalance in cholesterol influx and efflux?
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Which vitamin is synthesized from cholesterol?
Which vitamin is synthesized from cholesterol?
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What is the primary mechanism by which bile acid sequestrants reduce LDL levels?
What is the primary mechanism by which bile acid sequestrants reduce LDL levels?
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Which of the following is NOT a side effect associated with the pharmacological use of niacin?
Which of the following is NOT a side effect associated with the pharmacological use of niacin?
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What transcriptional mechanism regulates the synthesis of HMG-CoA reductase mRNA?
What transcriptional mechanism regulates the synthesis of HMG-CoA reductase mRNA?
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What effect do bile acid sequestrants have on the LDL-receptors?
What effect do bile acid sequestrants have on the LDL-receptors?
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How do plant stanols differ from plant sterols?
How do plant stanols differ from plant sterols?
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What is a common proposed mechanism for how niacin influences lipid levels?
What is a common proposed mechanism for how niacin influences lipid levels?
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What role does SREBP play in cholesterol metabolism?
What role does SREBP play in cholesterol metabolism?
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What is one of the significant outcomes of increasing hepatic synthesis of bile acids when using bile acid sequestrants?
What is one of the significant outcomes of increasing hepatic synthesis of bile acids when using bile acid sequestrants?
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What is the primary role of the cytosolic HMG-CoA synthase?
What is the primary role of the cytosolic HMG-CoA synthase?
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Which step in bile acid synthesis is considered the rate-limiting step?
Which step in bile acid synthesis is considered the rate-limiting step?
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What compound is primarily formed from the condensation of five-carbon isoprenoids?
What compound is primarily formed from the condensation of five-carbon isoprenoids?
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What is a common cause of cholesterol gallstones?
What is a common cause of cholesterol gallstones?
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What effect does conjugation of bile acids have on their function?
What effect does conjugation of bile acids have on their function?
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How is cholesterol transported to extra-hepatic tissues?
How is cholesterol transported to extra-hepatic tissues?
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What is the end product of the cyclization of squalene?
What is the end product of the cyclization of squalene?
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Which of the following describes bile acid action in the gut?
Which of the following describes bile acid action in the gut?
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What is the primary site for de novo synthesis of cholesterol?
What is the primary site for de novo synthesis of cholesterol?
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Which enzyme is responsible for esterifying cholesterol in lipid droplets?
Which enzyme is responsible for esterifying cholesterol in lipid droplets?
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What is the rate limiting step in cholesterol synthesis?
What is the rate limiting step in cholesterol synthesis?
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Which source predominantly generates Acetyl-CoA for cholesterol synthesis?
Which source predominantly generates Acetyl-CoA for cholesterol synthesis?
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What is required in the synthesis of cholesterol aside from Acetyl-CoA?
What is required in the synthesis of cholesterol aside from Acetyl-CoA?
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Which statement about the brain and cholesterol is true?
Which statement about the brain and cholesterol is true?
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Which fatty acids are most commonly esterified to cholesterol?
Which fatty acids are most commonly esterified to cholesterol?
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Which enzyme esterifies cholesterol that is associated with HDL?
Which enzyme esterifies cholesterol that is associated with HDL?
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What is the role of bile salts in lipid absorption?
What is the role of bile salts in lipid absorption?
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Which of the following is NOT a method of regulating HMG-CoA reductase activity?
Which of the following is NOT a method of regulating HMG-CoA reductase activity?
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How does glucagon affect HMG-CoA reductase activity?
How does glucagon affect HMG-CoA reductase activity?
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What is the mechanism by which statins lower LDL-C levels?
What is the mechanism by which statins lower LDL-C levels?
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Which dietary approach is effective for treating hypercholesterolemia?
Which dietary approach is effective for treating hypercholesterolemia?
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What is a proposed effect of hyperinsulinemia on HMG-CoA reductase activity?
What is a proposed effect of hyperinsulinemia on HMG-CoA reductase activity?
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How do plant sterols and stanols impact cholesterol absorption?
How do plant sterols and stanols impact cholesterol absorption?
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What is a significant consequence of inhibiting cholesterol synthesis in cells?
What is a significant consequence of inhibiting cholesterol synthesis in cells?
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What is one proposed mechanism by which niacin reduces lipid levels in the bloodstream?
What is one proposed mechanism by which niacin reduces lipid levels in the bloodstream?
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What effect do bile acid sequestrants have on hepatic cholesterol levels?
What effect do bile acid sequestrants have on hepatic cholesterol levels?
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What is a common side effect of using pharmacological doses of niacin?
What is a common side effect of using pharmacological doses of niacin?
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How does the mechanism of action of bile acid sequestrants facilitate the reduction of LDL cholesterol levels?
How does the mechanism of action of bile acid sequestrants facilitate the reduction of LDL cholesterol levels?
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What role do sterol-regulatory element-binding proteins (SREBPs) play in cholesterol metabolism?
What role do sterol-regulatory element-binding proteins (SREBPs) play in cholesterol metabolism?
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Which of the following accurately describes the difference between plant stanols and plant sterols?
Which of the following accurately describes the difference between plant stanols and plant sterols?
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What is the primary location of cholesterol synthesis within the body?
What is the primary location of cholesterol synthesis within the body?
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Which enzyme is responsible for transferring fatty acids to the C3 hydroxyl group of cholesterol?
Which enzyme is responsible for transferring fatty acids to the C3 hydroxyl group of cholesterol?
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What is the critical limiting factor in the rate of cholesterol synthesis?
What is the critical limiting factor in the rate of cholesterol synthesis?
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Which process is essential for transporting Acetyl-CoA from mitochondria to the cytosol for cholesterol synthesis?
Which process is essential for transporting Acetyl-CoA from mitochondria to the cytosol for cholesterol synthesis?
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What role does lecithin:cholesterol acyltransferase (LCAT) play in cholesterol metabolism?
What role does lecithin:cholesterol acyltransferase (LCAT) play in cholesterol metabolism?
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Which cofactors are required for the synthesis of cholesterol?
Which cofactors are required for the synthesis of cholesterol?
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What is the first step in the synthesis of mevalonate from Acetyl-CoA?
What is the first step in the synthesis of mevalonate from Acetyl-CoA?
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What is the significance of the brain in cholesterol metabolism?
What is the significance of the brain in cholesterol metabolism?
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Which fatty acids are commonly esterified to cholesterol during metabolism?
Which fatty acids are commonly esterified to cholesterol during metabolism?
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What is a common source of Acetyl-CoA necessary for cholesterol synthesis?
What is a common source of Acetyl-CoA necessary for cholesterol synthesis?
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What effect does glucagon have on the activity of HMG-CoA reductase?
What effect does glucagon have on the activity of HMG-CoA reductase?
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How do statins function as cholesterol-lowering drugs?
How do statins function as cholesterol-lowering drugs?
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What dietary change is recommended for effectively treating hypercholesterolemia?
What dietary change is recommended for effectively treating hypercholesterolemia?
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What role does dietary soluble fiber play in cholesterol metabolism?
What role does dietary soluble fiber play in cholesterol metabolism?
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What impact does hyperinsulinemia have on HMG-CoA reductase activity?
What impact does hyperinsulinemia have on HMG-CoA reductase activity?
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What is a proposed effect of consuming therapeutic doses of plant sterols and stanols?
What is a proposed effect of consuming therapeutic doses of plant sterols and stanols?
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What energy consideration is associated with cholesterol synthesis?
What energy consideration is associated with cholesterol synthesis?
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What happens to the intracellular cholesterol pool when cholesterol synthesis is inhibited?
What happens to the intracellular cholesterol pool when cholesterol synthesis is inhibited?
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Which factor is critical for the absorption of lipids in the intestine?
Which factor is critical for the absorption of lipids in the intestine?
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What is one of the primary functions of cholesterol in human physiology?
What is one of the primary functions of cholesterol in human physiology?
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Which of the following is a characteristic feature of the cholesterol molecule structure?
Which of the following is a characteristic feature of the cholesterol molecule structure?
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How is the balance between cholesterol influx and efflux typically described?
How is the balance between cholesterol influx and efflux typically described?
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What contributes to the potential risk of atherosclerosis regarding cholesterol?
What contributes to the potential risk of atherosclerosis regarding cholesterol?
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What is the major form of cholesterol found in cellular membranes?
What is the major form of cholesterol found in cellular membranes?
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What strongly influences the regulation of HMG-CoA reductase?
What strongly influences the regulation of HMG-CoA reductase?
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Which statement is true regarding the dietary treatment strategies for hyperlipidemias?
Which statement is true regarding the dietary treatment strategies for hyperlipidemias?
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What is the fate of excess cholesterol in the body?
What is the fate of excess cholesterol in the body?
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What is the preferred source of Acetyl-CoA utilized in cholesterol synthesis?
What is the preferred source of Acetyl-CoA utilized in cholesterol synthesis?
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What is the main outcome of squalene oxidation and cyclization in cholesterol synthesis?
What is the main outcome of squalene oxidation and cyclization in cholesterol synthesis?
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Which statement accurately describes the function of conjugated bile acids?
Which statement accurately describes the function of conjugated bile acids?
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What is the primary regulatory factor for the activity of 7α-hydroxylase in bile acid synthesis?
What is the primary regulatory factor for the activity of 7α-hydroxylase in bile acid synthesis?
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What is one major role of ACAT in cholesterol metabolism?
What is one major role of ACAT in cholesterol metabolism?
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Which process describes the synthesis of bile acids from cholesterol in the liver?
Which process describes the synthesis of bile acids from cholesterol in the liver?
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What is a critical consequence of bile becoming supersaturated with cholesterol?
What is a critical consequence of bile becoming supersaturated with cholesterol?
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What compound is produced as a result of the phosphorylation and decarboxylation of mevalonic acid?
What compound is produced as a result of the phosphorylation and decarboxylation of mevalonic acid?
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What is the primary storage site for bile acids after synthesis in the liver?
What is the primary storage site for bile acids after synthesis in the liver?
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What is the fate of cholesterol after it is esterified?
What is the fate of cholesterol after it is esterified?
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Which end product results from the condensation of two 15-carbon farnesyl pyrophosphate units?
Which end product results from the condensation of two 15-carbon farnesyl pyrophosphate units?
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Study Notes
Cholesterol Metabolism
-
Learning Objectives:
- Describe cholesterol structure and function
- List key intermediates in de novo synthesis.
- Discuss regulation of intracellular cholesterol, including how HMG-CoA reductase is regulated.
- Explain cholesterol metabolism and excretion.
- Detail bile acid circulation and enterohepatic circulation.
- Describe dietary strategies for hyperlipidemia (high cholesterol).
Structure of Cholesterol
- Cholesterol has four fused hydrocarbon rings (A-D), a hydroxyl group at C3, a double bond between C5 and C6, and a hydrocarbon chain at C17 with methyl groups at C10 and C13.
Cholesterol Functions
- Cholesterol is a component of cell membranes.
- It's a precursor to bile acids, vitamin D, and steroid hormones.
- Humans can't metabolize cholesterol into carbon dioxide and water.
- Gradual cholesterol deposition in tissues can lead to plaque formation, causing blood vessel narrowing (atherosclerosis), which increases the risk of heart, brain, and peripheral vascular diseases.
Free and Esterified Cholesterol
- Most cellular cholesterol is in free form; dietary cholesterol is primarily free when it reaches the liver.
- Most circulating cholesterol is esterified to long-chain fatty acids (like oleic and linoleic).
- Esterification occurs to transport cholesterol in the blood.
Esterified Cholesterol
- Two main enzymes esterify cholesterol:
- Acyl-CoA:cholesterol acyltransferase (ACAT): an ER membrane protein, transferring fatty acids from fatty acyl-CoA to cholesterol's C3 hydroxyl group.
- Lecithin:cholesterol acyltransferase (LCAT): an extracellular enzyme esterifying cholesterol associated with HDL.
De Novo Synthesis of Cholesterol
- Primary site: liver (1 gram/day) within smooth endoplasmic reticulum (SER).
- Secondary sites: intestine, adrenal cortex, ovaries, testes and others.
- Brain has high cholesterol content synthesized in the central nervous system, particularly during active myelination.
- All carbons originate from acetyl-CoA.
- HMG-CoA reductase is the rate-limiting step and is regulated by: transcriptional control, proteolytic degradation, and covalent modification (phosphorylation/dephosphorylation).
- Synthesis requires 18 acetyl-CoA, 16 NADPH, and 36 ATP.
Sources of Acetyl-CoA
- Pyruvate dehydrogenase reaction from glucose
- Ethanol
Fate of Hepatic Cholesterol
- Transport to extra-hepatic tissues via esterification by ACAT and incorporation into VLDL.
- Direct excretion into bile as biliary cholesterol (precipitate as gallstones if bile becomes supersaturated).
- Bile acid synthesis and excretion into bile.
Synthesis of Bile Acids
- Synthesized in the liver, stored in the gallbladder.
- Released into the gut aiding lipid, cholesterol, and fat-soluble vitamin absorption.
- The 7α-hydroxylase (CYP7A1) is the rate-limiting step, regulated by bile acid and salt concentration, aiding conversion of cholesterol to bile acids.
- Bile acids are conjugated (to glycine or taurine) becoming emulsifiers for lipid digestion and absorption.
Fate of Bile Salts
- Enterohepatic recirculation: >95% of bile salts are reabsorbed in the intestine and returned to the liver.
- Bacteria in the gut deconjugate and dehydroxylate bile salts, exiting the body largely through feces.
Regulation of HMG-CoA Reductase Activity
- Cholesterol synthesis is a complex and energy-expensive process regulated by:
- Transcriptional regulation (controlling mRNA synthesis) involving sterol-regulatory element-binding proteins (SREBPs).
- Proteolytic degradation (controlling enzyme amount).
- Covalent modification via phosphorylation/dephosphorylation, regulated by hormones like insulin and glucagon.
- Hormone regulation through insulin/glucagon involves phosphorylation/dephosphorylation.
Cholesterol-Lowering Drugs (HMG-CoA Reductase Inhibitors)
- Statins—structural analogs of HMG-CoA acting as competitive inhibitors.
- 18-55% reduction in LDL cholesterol, increased HDL cholesterol levels, and decreased TG levels.
- Mechanism of action by inhibiting HMG-CoA reductase, curbing cholesterol synthesis, and raising LDL receptor synthesis, lowering LDL-C levels in the body.
Plant Stanols and Sterols
- Plant stanols and sterols are structurally similar to cholesterol but aren't absorbed as readily, thus interfering with cholesterol absorption.
Bile Acid Sequestrants
- Cholestyramine: reduces LDL by 15–30%, interfering with bile acid reabsorption, forcing the liver to convert cholesterol into bile acids to compensate.
- Side effects: GI distress, constipation, decreased absorption of fat-soluble vitamins, and other drugs.
Pharmacological doses of Niacin
- 5–25% reduction in LDL—increases HDL and decreases LDL and TG.
- Proposed mechanism: reduced VLDL synthesis, decreased lipolysis in adipose tissue, and increased lipoprotein lipase activity.
- Side effects: flushing, itching, GI distress, hyperglycemia, hyperuricemia, and hepatotoxicity.
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Description
This quiz covers the structure, functions, and metabolism of cholesterol, including its synthesis and regulation. Learn about key intermediates, bile acid circulation, and dietary strategies to manage hyperlipidemia. Ideal for students studying biochemistry or health sciences.
