Unit 19 Question Bank
Format note: the TMU Biochemistry paper gives five suggested
answers (A–E), not four — these MCQs match that. Items tagged TMU 2019 or
TMU 2020/21 come from the real papers. Answers are verified against Harper's
Illustrated Biochemistry; the "marking schemes" in the source folder are other students'
answer sheets, not official, so they are never used as the authority.
0 / 25 answered
1All the carbon atoms of cholesterol are provided by ( ).
Answer: E
Every one of the 27 carbons. Cholesterol synthesis takes place in the cytosol, and NADPH provides the reducing equivalents — the same currency as fatty acid synthesis, from the same pentose phosphate pathway. Two very different molecules built from the same two ingredients.Harper's ch.26, p.268
2The rate-limiting enzyme of cholesterol biosynthesis is ( ).
Answer: A
Keep the three HMG-CoA enzymes apart. Reductase — cytosolic, rate-limiting for cholesterol, the statin target. Synthase — mitochondrial, regulatory for ketogenesis (Unit 17). Lyase — cleaves HMG-CoA to acetoacetate. Note that HMG-CoA synthase and lyase exist in both compartments, but only the mitochondrial pool is ketogenic.Harper's ch.26, pp.268–269
3Cholesterol synthesis proceeds through five stages. The correct order is ( ).
Answer: B
Track the carbon count and the sequence tells its own story: C2 → C6 mevalonate → C5 isoprenoid → C30 squalene → C30 lanosterol → C27 cholesterol. Note that squalene is the first molecule with the full carbon skeleton and lanosterol the first with the steroid ring — cyclisation happens between them.Harper's ch.26, pp.268–270
4HMG-CoA reductase is inhibited by ( ).
Answer: C
The statins — simvastatin, atorvastatin and their relatives — are competitive inhibitors of the enzyme. And there is a second-order effect that matters more than the first: lowering intracellular cholesterol de-represses LDL-receptor synthesis, so the liver clears more LDL from plasma. The drug lowers plasma LDL mainly by making cells hungrier for it.Harper's ch.26, pp.269, 274
5HMG-CoA reductase activity is regulated by all the following EXCEPT ( ).
Answer: D
Mevalonate is the product, and products do not activate their own synthesis. Note how many independent layers of control this one enzyme carries — transcription, degradation, phosphorylation and feedback inhibition. That is the signature of a true rate-limiting step. Insulin and thyroid hormone increase activity; glucagon and glucocorticoids decrease it.Harper's ch.26, pp.271–273
6SREBP (sterol regulatory element-binding protein) ( ).
Answer: E
The mechanism is a small marvel: SREBP is held in the ER membrane and, when sterols are scarce, is escorted to the Golgi and cleaved, releasing a fragment that migrates to the nucleus. One sensor, two responses — make more, and import more.Harper's ch.26, p.272
7The principal route of cholesterol EXCRETION from the body is ( ).
Answer: A
This is the fact behind an important negative one: the steroid nucleus cannot be broken down to CO₂ and water in the body. Cholesterol can only be excreted, or converted into something else that is excreted. About 1 g per day is eliminated, roughly half as bile acids and half as neutral steroids.Harper's ch.26, p.273
8The rate-limiting enzyme of bile acid synthesis is ( ).
Answer: B
Note the parallel with the synthetic pathway: cholesterol feedback-inhibits HMG-CoA reductase to reduce production, and bile acids feedback-inhibit 7α-hydroxylase to reduce disposal. Both ends of cholesterol balance are under product feedback. Ascorbic acid deficiency impairs this enzyme, which is why guinea pigs with scurvy develop cholesterol accumulation.Harper's ch.26, p.273
9The primary bile acids are ( ), and they are formed in ( ).
Answer: C
The secondary bile acids — deoxycholic and lithocholic — are made by intestinal bacteria from the primary ones. Before secretion the primary acids are conjugated with glycine or taurine, which lowers their pKa and keeps them ionised and therefore better detergents at intestinal pH.Harper's ch.26, p.273
10The enterohepatic circulation of bile acids means that ( ).
Answer: D
Only 0.5 g per day is lost in the feces, yet the pool cycles six to ten times a day. That efficiency is the target of an entire drug class: bile acid sequestrants such as cholestyramine bind bile acids in the gut, force the liver to make more from cholesterol, and so lower plasma cholesterol.Harper's ch.26, pp.273–274
11Cholesterol is esterified inside cells by ( ) and in plasma by ( ).
Answer: E
ACAT — acyl-CoA:cholesterol acyltransferase — is intracellular and uses acyl-CoA; it stores surplus cholesterol as ester droplets and is activated by cholesterol itself. LCAT is in plasma, uses a fatty acid from phosphatidylcholine, is activated by apo A-I, and drives reverse cholesterol transport. Same chemistry, opposite purposes.Harper's ch.26, p.271 · Harper's ch.25, p.261
12Which is NOT a physiological product derived from cholesterol?
Answer: A
Prostaglandins come from arachidonic acid, a C20 polyunsaturated fatty acid (Unit 15) — not from the steroid nucleus. Everything else on the list is a genuine cholesterol derivative, which is why cholesterol is indispensable despite its role in disease: it is also a major component of the plasma membrane, where it modulates fluidity.Harper's ch.26, p.267 · Harper's ch.23
13About how much cholesterol is synthesised daily in the body, compared with the dietary intake?
Answer: B
Endogenous synthesis exceeds the dietary supply — which is precisely why dietary restriction alone has a modest effect on plasma cholesterol, and why inhibiting synthesis with statins works so much better. Virtually all tissues can synthesise cholesterol, but the liver, intestine, adrenal cortex and reproductive tissues contribute most.Harper's ch.26, pp.267–268
14Plasma cholesterol may be lowered by dietary measures including ( ).
Answer: C
Note the asymmetry: the TYPE of fat matters more than dietary cholesterol itself. Trans fatty acids raise LDL and lower HDL — the worst of both. Soluble fibre such as oat bran works by binding bile acids and increasing their fecal loss, the same mechanism as cholestyramine.Harper's ch.26, p.274
15Familial hypercholesterolemia leads to premature atherosclerosis because ( ).
Answer: D
Trace the consequences forward: LDL persists in plasma, becomes oxidatively modified, is taken up by macrophage scavenger receptors — which are NOT down-regulated by cholesterol — and the macrophages become foam cells, the earliest lesion of the atherosclerotic plaque. The unregulated pathway is what makes the disease.Harper's ch.26, pp.274–275 · Harper's ch.25
16Serum cholesterol correlates with the incidence of atherosclerosis. Which correlation is INVERSE?
Answer: E
The mechanistic reason is reverse cholesterol transport — HDL is the only particle carrying cholesterol away from the arterial wall towards the liver, the only organ that can excrete it. Lp(a) is an LDL-like particle whose apo(a) resembles plasminogen, and it may promote thrombosis; its correlation is positive.Harper's ch.26, pp.274–275
17Ezetimibe lowers plasma cholesterol by ( ).
Answer: A
Worth grouping the drug mechanisms by where they intervene: statins block synthesis; ezetimibe blocks absorption; cholestyramine blocks reabsorption of bile acids. Three separate points on the same balance sheet, which is why they combine well.Harper's ch.26, p.274
18The conversion of squalene to lanosterol requires ( ).
Answer: B
This is the cyclisation — the step at which a long open chain folds into the four fused rings of the steroid nucleus. From lanosterol, some 19 further steps remove three methyl groups to reach the 27-carbon cholesterol. It requires molecular oxygen, so cholesterol synthesis is an aerobic process.Harper's ch.26, p.270
19Which statement about cholesterol in the plasma membrane is correct?
Answer: C
A single molecule acting as a fluidity buffer in both directions: it restrains the motion of fatty acyl chains when they are too fluid and prevents their tight packing when they are too rigid. It is also concentrated in lipid rafts and caveolae, membrane microdomains important in signalling.Harper's ch.26, p.267 · Harper's ch.40
20ACAT is activated by ( ).
Answer: D
Read this alongside the LDL-receptor story of Unit 18 and you have the cell's complete cholesterol response: incoming cholesterol inhibits HMG-CoA reductase (stop making), suppresses LDL-receptor synthesis (stop importing) and activates ACAT (store the surplus). Three actions, one signal — this is the answer to “how does a cell regulate its cholesterol?”Harper's ch.26, p.271 · Harper's ch.25, p.259
21Cholesterol balance in the tissues is achieved by all of the following EXCEPT ( ).
Answer: E
The ring system cannot be degraded in the body. Cholesterol has only two exits — conversion to bile acids, or excretion as neutral steroids — and both require it to reach the liver first. This one negative fact is what makes reverse cholesterol transport, and hence HDL, so important.Harper's ch.26, pp.271, 273
22Gallstones of the cholesterol type form when ( ).
Answer: A
Cholesterol is insoluble in water and is held in bile only as mixed micelles with bile acids and phosphatidylcholine. Alter the ratio — more cholesterol, or fewer bile acids — and it crystallises out. Treatment with chenodeoxycholic acid works by restoring the ratio.Harper's ch.26, p.274
23Mevalonate is formed from HMG-CoA by a reaction that uses ( ).
Answer: B
The reduction of the thioester to a primary alcohol needs four electrons — hence two NADPH. Note that this is the rate-limiting and irreversible step, and NADPH again comes from the pentose phosphate pathway, the same source that funds fatty acid synthesis.Harper's ch.26, pp.268–269
24Which of these correctly describes the origin of the intracellular cholesterol pool?
Answer: C
Reciprocal regulation is the point: cholesterol arriving in LDL shuts down synthesis, and a shortage of it turns synthesis and receptor expression back on through SREBP. The cell holds its cholesterol content near constant regardless of supply — which is exactly why dietary restriction alone moves plasma cholesterol so little.Harper's ch.26, pp.271–272
25Approximately what proportion of the cholesterol excreted daily leaves as bile acids?
Answer: D
Of roughly 1 g per day, about 0.5 g is converted to bile acids and the remainder is excreted as neutral steroids. Much of the biliary cholesterol is reabsorbed, and a good deal of that formed in the gut is coprostanol, produced by intestinal bacteria.Harper's ch.26, p.273
1 Cholesterol — 3′+
A 27-carbon amphipathic steroid alcohol, a major component of the plasma membrane where it modulates fluidity, and the precursor of bile acids, steroid hormones and vitamin D.
All its carbon atoms are provided by acetyl-CoA. Synthesis occurs in the cytosol of virtually all tissues — chiefly liver, intestine, adrenal cortex and reproductive tissues — with NADPH supplying reducing equivalents. About 700 mg is synthesised daily, exceeding the dietary intake.
The steroid nucleus cannot be degraded to CO₂ and water in the body. Cholesterol is eliminated only by conversion to bile acids or excretion as neutral steroids, about 1 g per day, roughly half by each route.Harper's ch.26, pp.267–273
All its carbon atoms are provided by acetyl-CoA. Synthesis occurs in the cytosol of virtually all tissues — chiefly liver, intestine, adrenal cortex and reproductive tissues — with NADPH supplying reducing equivalents. About 700 mg is synthesised daily, exceeding the dietary intake.
The steroid nucleus cannot be degraded to CO₂ and water in the body. Cholesterol is eliminated only by conversion to bile acids or excretion as neutral steroids, about 1 g per day, roughly half by each route.Harper's ch.26, pp.267–273
2 HMG-CoA reductase — 3′+
The rate-limiting enzyme of cholesterol biosynthesis, in the endoplasmic reticulum membrane, catalysing the irreversible reduction of HMG-CoA to mevalonate using two NADPH.
Regulated at four levels: transcription, via SREBP — activated when cellular sterol is low; regulated degradation of the enzyme protein; covalent modification — phosphorylation inactivates it; and feedback inhibition by cholesterol, both dietary and that delivered in LDL. Insulin and thyroid hormone increase activity; glucagon and glucocorticoids decrease it.
It is the target of the statins, which are competitive inhibitors. They lower plasma LDL chiefly by an indirect route: falling intracellular cholesterol de-represses LDL-receptor synthesis, so the liver clears more LDL from the blood.
Do not confuse with HMG-CoA SYNTHASE, the mitochondrial regulatory enzyme of ketogenesis.Harper's ch.26, pp.268–274
Regulated at four levels: transcription, via SREBP — activated when cellular sterol is low; regulated degradation of the enzyme protein; covalent modification — phosphorylation inactivates it; and feedback inhibition by cholesterol, both dietary and that delivered in LDL. Insulin and thyroid hormone increase activity; glucagon and glucocorticoids decrease it.
It is the target of the statins, which are competitive inhibitors. They lower plasma LDL chiefly by an indirect route: falling intracellular cholesterol de-represses LDL-receptor synthesis, so the liver clears more LDL from the blood.
Do not confuse with HMG-CoA SYNTHASE, the mitochondrial regulatory enzyme of ketogenesis.Harper's ch.26, pp.268–274
3 Bile acids — 3′+
C24 steroid acids formed from cholesterol in the liver, the principal route of cholesterol excretion and the detergents that emulsify dietary lipid.
The primary bile acids are cholic acid and chenodeoxycholic acid; 7α-hydroxylase is the rate-limiting enzyme, and it is feedback-inhibited by bile acids. Before secretion they are conjugated with glycine or taurine, which keeps them ionised and therefore better detergents at intestinal pH. Secondary bile acids — deoxycholic and lithocholic — are produced by intestinal bacteria.
Enterohepatic circulation: 98–99% is reabsorbed in the ileum and returned to the liver, the pool cycling six to ten times a day, with only about 0.5 g lost daily in the feces. Interrupting this cycle with bile acid sequestrants such as cholestyramine forces the liver to convert more cholesterol to bile acids and so lowers plasma cholesterol.Harper's ch.26, pp.273–274
The primary bile acids are cholic acid and chenodeoxycholic acid; 7α-hydroxylase is the rate-limiting enzyme, and it is feedback-inhibited by bile acids. Before secretion they are conjugated with glycine or taurine, which keeps them ionised and therefore better detergents at intestinal pH. Secondary bile acids — deoxycholic and lithocholic — are produced by intestinal bacteria.
Enterohepatic circulation: 98–99% is reabsorbed in the ileum and returned to the liver, the pool cycling six to ten times a day, with only about 0.5 g lost daily in the feces. Interrupting this cycle with bile acid sequestrants such as cholestyramine forces the liver to convert more cholesterol to bile acids and so lowers plasma cholesterol.Harper's ch.26, pp.273–274
4 The mevalonate pathway — 2′+
The cytosolic pathway of cholesterol biosynthesis from acetyl-CoA, in five stages:
1 · Acetyl-CoA → HMG-CoA → mevalonate (C6), by HMG-CoA reductase with 2 NADPH — the rate-limiting and irreversible step.
2 · Mevalonate → isoprenoid units (C5), with loss of CO₂ and using ATP.
3 · Six isoprenoid units condense to squalene (C30) — the first molecule with the complete carbon skeleton.
4 · Squalene cyclises to lanosterol, requiring O₂ and NADPH — the first molecule with the steroid ring system.
5 · Lanosterol → cholesterol (C27) over some 19 steps, with loss of three methyl groups.
Isoprenoid intermediates also give rise to dolichol, ubiquinone and farnesylated proteins.Harper's ch.26, pp.268–271
1 · Acetyl-CoA → HMG-CoA → mevalonate (C6), by HMG-CoA reductase with 2 NADPH — the rate-limiting and irreversible step.
2 · Mevalonate → isoprenoid units (C5), with loss of CO₂ and using ATP.
3 · Six isoprenoid units condense to squalene (C30) — the first molecule with the complete carbon skeleton.
4 · Squalene cyclises to lanosterol, requiring O₂ and NADPH — the first molecule with the steroid ring system.
5 · Lanosterol → cholesterol (C27) over some 19 steps, with loss of three methyl groups.
Isoprenoid intermediates also give rise to dolichol, ubiquinone and farnesylated proteins.Harper's ch.26, pp.268–271
1
Describe the biosynthesis of cholesterol and how it is regulated.
8′
Where and from what
Cholesterol synthesis occurs in the cytosol of virtually all tissues — chiefly liver, intestine, adrenal cortex and reproductive tissues. All 27 carbon atoms are provided by acetyl-CoA, and NADPH supplies the reducing equivalents, largely from the pentose phosphate pathway. About 700 mg is made daily, more than the diet supplies.
The five stages
- Acetyl-CoA → mevalonate. Two acetyl-CoA condense to acetoacetyl-CoA, a third is added by HMG-CoA synthase to give HMG-CoA, and HMG-CoA reductase reduces this to mevalonate (C6) using two NADPH. This is the rate-limiting and irreversible step. Note that the cytosolic HMG-CoA pool is distinct from the mitochondrial pool used for ketogenesis.
- Mevalonate → isoprenoid units (C5), by successive phosphorylations with ATP and a decarboxylation.
- Six isoprenoid units → squalene (C30) — the first molecule with cholesterol's complete carbon skeleton, though still an open chain.
- Squalene → lanosterol. Squalene epoxidase (requiring O₂ and NADPH) and oxidosqualene:lanosterol cyclase fold the chain into the four fused rings of the steroid nucleus. Cholesterol synthesis is therefore aerobic.
- Lanosterol → cholesterol (C27), over about 19 steps, with the loss of three methyl groups.
The isoprenoid intermediates are not exclusive to cholesterol — they also yield dolichol, ubiquinone and the farnesyl groups that anchor certain proteins to membranes. That is why statins have effects beyond cholesterol lowering.
Regulation — four independent layers on one enzyme
- Transcription. When cellular sterol is low, SREBP — held in the ER membrane — is escorted to the Golgi, cleaved, and its fragment enters the nucleus to increase transcription of both HMG-CoA reductase and the LDL receptor. One sensor, two responses: make more, and import more.
- Enzyme degradation. Sterols accelerate degradation of the reductase protein.
- Covalent modification. Phosphorylation inactivates the enzyme; insulin and thyroid hormone increase activity, glucagon and glucocorticoids decrease it. Cholesterol synthesis is thus a fed-state activity, like fatty acid synthesis.
- Feedback inhibition by cholesterol, whether dietary or delivered in LDL.
The cell's complete cholesterol response
Cholesterol released from LDL in the lysosome does three things at once: it inhibits HMG-CoA reductase, suppresses synthesis of the LDL receptor, and activates ACAT to store the surplus as cholesteryl ester. Synthesis and uptake are reciprocally regulated, so the cell holds its cholesterol content nearly constant — which is precisely why dietary restriction alone lowers plasma cholesterol so little, and why inhibiting synthesis with statins works so much better.
Marking guide: cytosolic location, acetyl-CoA origin, NADPH 1 · the five stages in order with the correct carbon counts 3 · HMG-CoA reductase named as rate-limiting, with 2 NADPH 1 · at least three regulatory mechanisms 2 · the reciprocal relationship between synthesis and LDL uptake 1.
2
How is cholesterol excreted from the body, and how can plasma cholesterol be lowered therapeutically?
5′
Why excretion is the only option
The steroid nucleus cannot be broken down to CO₂ and water in the body. Cholesterol has therefore only two exits, and both require it to reach the liver — the only organ that can dispose of it. Roughly 1 g per day is eliminated, about half as bile acids and half as neutral steroids.
Conversion to bile acids
7α-hydroxylase is the rate-limiting enzyme, and it is feedback-inhibited by bile acids — the mirror image of cholesterol's inhibition of HMG-CoA reductase, so both ends of the balance are under product control. The primary bile acids, cholic and chenodeoxycholic acid, are conjugated with glycine or taurine before secretion, which keeps them ionised and hence better detergents at intestinal pH. Intestinal bacteria convert them to the secondary bile acids, deoxycholic and lithocholic.
The enterohepatic circulation
98–99% of secreted bile acids are reabsorbed in the ileum and returned to the liver, the pool cycling six to ten times a day, so only about 0.5 g is lost daily in the feces. This extreme efficiency is what makes the circulation a drug target.
Therapeutic approaches — grouped by where they act
- Block synthesis — statins. Competitive inhibitors of HMG-CoA reductase. Their main effect is indirect: falling intracellular cholesterol de-represses LDL-receptor synthesis, so hepatocytes clear more LDL from plasma.
- Block absorption — ezetimibe, which inhibits intestinal cholesterol uptake via the NPC1L1 transporter.
- Block reabsorption — bile acid sequestrants such as cholestyramine, and soluble dietary fibre such as oat bran. Both bind bile acids in the lumen and increase their fecal loss, forcing the liver to convert more cholesterol into bile acids.
- Diet. Replacing saturated with polyunsaturated and monounsaturated fatty acids lowers plasma cholesterol; trans fatty acids raise LDL and lower HDL. The type of fat matters more than the dietary cholesterol content, because endogenous synthesis exceeds intake and adjusts to compensate.
These act at three separate points on the same balance sheet — synthesis, absorption and reabsorption — which is why they are effective in combination.
Why it matters
LDL cholesterol correlates positively and HDL inversely with the incidence of atherosclerosis. LDL that persists in plasma becomes oxidatively modified and is taken up by macrophage scavenger receptors, which are not down-regulated by cholesterol; the macrophages become the foam cells of the early plaque.
Marking guide: the steroid nucleus cannot be degraded 1 · bile acid route with 7α-hydroxylase 1 · enterohepatic circulation with a figure 1 · at least three therapeutic mechanisms correctly explained 1.5 · LDL/HDL and atherosclerosis 0.5.