Question 1

You have been studying the pathway of cholesterol biosynthesis using a cell line derived from a human hepatoma. You discover that, unlike in nontransformed liver cells, the addition of oxysterols, such as 25-hydroxycholesterol, does not lead to reduced measurements of newly synthesized cholesterol. These observations indicate that normal regulation of an enzyme in cholesterol biosynthesis is defective in these cancer cells. Which of the following enzymes is the most likely candidate for this loss of regulation?

A) acetoacetyl-CoA thiolase (ACAT2)
B) 7-dehydrocholesterol reductase (DHCR7)
C) HMG-CoA reductase (HMGR)
D) HMG-CoA synthase
E) mevalonate kinase

HMG-CoA reductase (HMGR)

Accepted Answer

HMG-CoA reductase (HMGR) is the rate-limiting enzyme in cholesterol biosynthesis and is normally regulated by oxysterols. In cancer cells, this regulation is often lost, leading to increased cholesterol synthesis.  Oxysterols regulate the activity of the transcription factor SREBP-1c. When oxysterol or cholesterol levels are elevated, there is an inhibition of the release of SREBP-1c from the Golgi membrane, thereby, reducing the SREBP-1c-mediated transcriptional activation of numerous target genes including HMGR. Normal oxysterol regulation of SREBP-1c would lead to reduced cholesterol synthesis due, in part, to reduced expression of HMGR. Thus, continued transcriptional activation of target genes by SREBP-1c, even in the presence of oxysterols, would be measurable with continued cholesterol synthesis due to unregulated transcription of HMGR

Question 2

Activation of which of the following enzymes, involved in the regulation of cholesterol biogenesis, occurs in response to an altered ATP:ADP ratio?&#10;A) AMP-activated kinase (AMPK)&#10;B) HMG-CoA reductase phosphatase&#10;C) protein phosphatase 2C&#10;D) protein phosphatase inhibitor-1&#10;E) protein kinase A (PKA)

Accepted Answer

AMP-activated kinase (AMPK) is activated in response to an increased AMP:ATP ratio, indicating low energy status, and it regulates cholesterol biogenesis by phosphorylating and inhibiting HMG-CoA reductase.  Regulation of HMG-CoA reductase (HMGR) is controlled primarily by a short-term regulatory cascade that results in phosphorylation of the enzyme. Once phosphorylated, HMGR is much less active and thus, cholesterol biosynthesis will be reduced. In order to return to a more active state, the phosphorylated sites on HMGR must be dephosphorylated. All of the enzyme choices listed are involved in regulation of HMGR activity, however, only AMP-activated kinase (AMPK) activity is affected by alteration in the ATP:ADP ratio in cells. When ATP levels fall, AMP levels will rise and AMPK becomes fully activated. Phosphorylation of HMGR by AMPK results in reduced cholesterol synthesis, which results in reduced ATP consumption.

Question 3

The statin class of drugs that are currently used to control hypercholesterolemia function to lower circulating levels of cholesterol by which of the following mechanisms?&#10;A) increasing the elimination of bile acids leading to increased diversion of cholesterol into bile acid production&#10;B) increasing the synthesis of apoB-100 resulting in increased elimination of cholesterol through the action of low-density lipoprotein (LDL) uptake by the liver&#10;C) decreasing the absorption of dietary cholesterol from the intestines&#10;D) inhibiting the interaction of LDLs with the hepatic LDL receptor&#10;E) inhibiting the rate-limiting step in cholesterol biosynthesis

Accepted Answer

Statins work by inhibiting HMG-CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis, thereby reducing cholesterol production in the liver.  The statins are a class of drugs derived from a compound originally isolated from red yeast (Monascus purpurus) used to ferment white rice (commonly called red yeast rice). The original compound isolated from red yeast is called lovastatin and marketed in the United States as the drug Mevacor. These drugs all inhibit the activity of the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase.

Question 4

Glucagon binding to liver cells induces an increase in intracellular cAMP concentration. The rate-limiting step in cholesterol biosynthesis is regulated as a consequence of this glucagon-mediated rise in cAMP. The effect of increased cAMP on the rate of cholesterol biosynthesis occurs because of which of the following?

A) AMP-regulated kinase (AMPK) is activated and directly phosphorylates human HMG-CoA reductase (HMGR), leading to an increase in the activity of the latter enzyme
B) cAMP-dependent protein kinase (PKA) is activated and directly phosphorylates HMGR, reducing the activity of the latter enzyme
C) PKA is activated and phosphorylates AMPK, which then phosphorylates and activates HMGR
D) PKA activation results in a reduced level of phosphate removal from HMG-CoA reductase so that the latter enzyme is kept less active.
E) the increased cAMP directly inhibits HMGR via allosteric interaction

Accepted Answer

Activation of PKA in hepatocytes will lead to increased phosphorylation of protein phosphatase inhibitor-1 (PPI-1) which will, in turn, lead to decreased activity of HMGR phosphatase. The reduced level of phosphate removal from HMGR will keep this enzyme in a less active state. The net effect will be a reduction in cholesterol biosynthesis, which will preserve ATP for use in gluconeogenesis, a primary response of liver to glucagon stimulation.

Question 5

You are studying cell line in which you discover that SREBP-2 is less tightly bound to the membranes of the ER. Examination of these cells shows no increase in cholesterol biosynthetic gene expression and no observable binding of SREBP-2 to the SREBPresponse element (SRE) of a known target gene. These observations can best be explained by a mutation in which of the following proteins?

A) Insig
B) SCAP
C) site 1 protease (S1P)
D) site 2 protease (S2P)
E) SREBP-1c

Accepted Answer

The most likely mutated protein in this case would be S2P. The reduced binding of SREBP-2 to ER membranes could most easily be explained by the normal activity of S1P. However, inability to fully release SREBP-2 would be due to ineffective S2P activity. Since S1P activity is likely normal, the mutation is not likely to be in Insig or SCAP either. The activity of SREBP-1c would have no bearing on the release of SREBP-2 from membranes.

Question 6

Which of the following proteins/enzymes is directly responsive to elevation in sterols, leading to a reduction in the transcriptional activation of the gene encoding HMG-CoA reductase?&#10;A) AMPK&#10;B) HMG-CoA reductase phosphatase&#10;C) SCAP&#10;D) site-1 protease (S1P)&#10;E) SREBP-1c

Accepted Answer

SCAP (SREBP cleavage-activating protein) senses sterol levels and regulates the activation of SREBP, which in turn affects the transcription of HMG-CoA reductase.  Sterols, particularly cholesterol, interact with SCAP and regulate the interaction of SCAP with the various SREBP proteins in the ER membrane. When sterols interact with SCAP, it results in SCAP retaining SREBP in the ER membrane such that it cannot migrate to the Golgi apparatus, where is would be acted upon by S1P. When sterol levels drop, the interaction between SCAP and SREBP is reduced and SREBP can migrate to the Golgi and be released from the membrane via the concerted actions of S1P and S2P.

Question 7

The major source of acetyl-CoA for the synthesis of cholesterol is derived from cytosolic citrate. Examination of a hepatic cell line shows that despite a loss of expression of ATP-citrate lyase (ACL), these cells continue to have the capacity to synthesize cholesterol. The most likely explanation for this observation is related to the fact that an additional pathway is active. Which of the following enzymes is involved in this pathway?

A) acetyl-CoA synthetase
B) acetyl-CoA acyltransferase 1 (ACAT1)
C) acetoacetyl-CoA synthetase
D) HMG-CoA reductase
E) HMG-CoA synthase

Accepted Answer

Acetoacetyl-CoA synthetase is involved in the pathway that generates acetyl-CoA from cytosolic citrate in the absence of ATP-citrate lyase. During ketogenesis, mitochondrial acetoacetate can diffuse to the cytosol where it is converted to acetoacetyl-CoA via the cytosolic enzyme, acetoacetyl-CoA synthetase. The resulting acetoacetylCoA could then serve as a direct substrate for incorporation into cholesterol. It is important to understand, however, that although this reaction process can occur, under conditions where ketogenesis is occurring in the liver the level of active HMGR would be significantly reduced.

Question 8

A 35-year-old man who has suffered a heart attack has a serum total cholesterol concentration of 500 mg/dL. His father died at 30 years of age from a massive heart attack, and one of his 2 younger siblings also has an increased serum concentration of total cholesterol. This patient most likely has a disorder caused by an autosomal dominant allele affecting which of the following components of cholesterol metabolism?

A) acyl-CoA acyltransferase (ACAT)
B) HMG-CoA reductase (HMGR)
C) low-density lipoprotein (LDL) receptor
D) lysosomal cholesterol esterase
E) plasma lipoprotein lipase

Accepted Answer

The patient's symptoms and family history suggest familial hypercholesterolemia, which is commonly caused by mutations in the LDL receptor gene, leading to impaired clearance of LDL cholesterol from the bloodstream. This condition is inherited in an autosomal dominant manner. The patient is most likely exhibiting symptoms related to familial hypercholesterolemia (FH). FH is an autosomal dominant inherited disease affecting the LDL receptor gene leading to significant elevation in plasma LDL levels and total cholesterol. Patients who are heterozygous for an FH allele will manifest with total serum cholesterol levels between 300 and 600 mg/dL.

Question 9

A 22-year-old man is being examined by his physician because he is concerned about growths on his eyelids. He is 180 cm (5 ft 11 in) tall and weighs 85 kg (188 lb); BMI is 26 kg/m2. Physical examination shows no other abnormalities except for xanthelasmas. Serum studies show a total cholesterol concentration of 300 mg/dL, HDL-cholesterol concentration of 37 mg/dL, and triglyceride concentration of 3500 mg/dL. Which of the following is the most likely cause of these findings?

A) essential fatty acid deficiency
B) hepatic lipase deficiency
C) HMG-CoA reductase deficiency
D) leptin deficiency
E) lipoprotein lipase deficiency

Accepted Answer

The patient's extremely high triglyceride levels and presence of xanthelasmas suggest a disorder in lipid metabolism, most likely lipoprotein lipase deficiency, which leads to impaired breakdown of triglycerides. The most telling finding in this patient is the massively elevated levels of triglycerides. Loss of, or reduced, activity of lipoprotein lipase would lead to a decreased capacity to remove fatty acids from the triglycerides in circulating lipoprotein particles, thus causing the significant increase in serum triglycerides.

Question 10

A 65-year-old man, who has been taking lovastatin to control his hypercholesterolemia, is found to have significantly reduced levels of glycoproteins in the plasma membranes of several cell types including red blood cells. The most likely cause of these changes in glycoprotein levels is a decrease in which of the following?

A) bile acids
B) cholesterol
C) coenzyme Q
D) dolichol phosphate
E) insulin

Accepted Answer

Dolichol phosphate is involved in the glycosylation of proteins, a process necessary for the formation of glycoproteins. Lovastatin, a statin, inhibits the synthesis of cholesterol and other isoprenoids, including dolichol phosphate, leading to reduced glycoprotein levels.  Inhibition of de novo cholesterol biosynthesis with the use of statin drugs, such as lovastatin, leads to reduction in the synthesis of several isoprenoid compounds such as dolichol phosphate. The reduction in dolichol production leads to inhibition of the ability to effectively carry off N-linked glycosylation of many cellular proteins (see Chapter 34).

Question 11

Which of the following enzymes would be expected to exert the greatest negative effect on the rate of cholesterol biosynthesis?&#10;A) acetyl-CoA carboxylase (ACC)&#10;B) AMP-regulated kinase (AMPK)&#10;C) cGMP-dependent protein kinase (PKG)&#10;D) HMG-CoA reductase (HMGR)&#10;E) malonyl-CoA decarboxylase (MCD)

Accepted Answer

The answer of Which of the following enzymes would be...

Question 12

Cholestyramine is a drug used to reduce serum cholesterol. It functions through binding bile salts and thereby, interferes with normal enterohepatic circulation of bile salts in the feces. Use of this drug would be associated with increased fecal amounts of which of the following compounds?

A) bilirubin
B) cholesterol
C) deoxycholate
D) glucuronate
E) palmitate

Accepted Answer

The answer of Cholestyramine is a drug used to reduce...

Question 13

Like all biosynthetic reactions, synthesis of cholesterol requires the input of energy in the form of ATP. In addition, cholesterol biosynthesis is dependent upon input of cytoplasmic precursor carbon atoms in the form of acetyl-CoA. Which of the following enzymes, each of which plays a role in cholesterol synthesis, is most dependent upon ATP for maximal activity?

A) citrate synthase
B) 7-dehydrocholesterol reductase (DHCR7)
C) HMG-CoA reductase (HMGR)
D) malate dehydrogenase
E) pyruvate carboxylase

Accepted Answer

The answer of Like all biosynthetic reactions, synthesis of cholesterol...

Question 14

You are examining a 6-month-old infant who presents with a series of distinctive craniofacial and limb abnormalities. These abnormalities include microcephaly, micrognathia, ptosis, cleft palate, short thumbs, and syndactyly of the second and third toes. You suspect the infant is suffering from Smith-Lemli-Opitz syndrome and order a confirmatory test that includes analysis of the activity of which of the following enzymes?

A) ATP-citrate lyase
B) 7-dehydrocholesterol reductase
C) HMG-CoA reductase
D) mevalonate kinase
E) pyruvate carboxylase

Accepted Answer

The answer of You are examining a 6-month-old infant who...

Question 15

Which of the following best explains the mechanism by which insulin action can result in increased hepatic cholesterol biosynthesis?&#10;A) insulin action results in phosphorylation of SCAP leading to increased release of SREBP-1c&#10;B) insulin action results in reduced levels of cAMP with consequent reduction in active PKA-mediated phosphorylation of SCAP&#10;C) insulin action results in reduced levels of cAMP with consequent reduction in active PKA-mediated phosphorylation of HMG-CoA reductase&#10;D) insulin action causes reduced levels of cAMP, which lead to reduced PKA-mediated phosphorylation of protein phosphatase inhibitor 1 (PPI-1)&#10;E) insulin action leads to tyrosine phosphorylation of AMPK, causing loss of the AMPK-mediated inhibition of HMG-CoA reductase

Accepted Answer

The answer of Which of the following best explains the...

Question 16

You are examining a patient you suspect is afflicted with Smith-Lemli-Opitz syndrome (SLOS), which is associated with mild to severe developmental abnormalities. Knowing that this disorder is the consequence of a defect in cholesterol biosynthesis, measurement of the blood levels of which of the following compounds would be most diagnostic of SLOS?

A) acetyl-CoA
B) 7-dehydrocholesterol
C) HMG-CoA
D) lanosterol
E) mevalonate

Accepted Answer

The answer of You are examining a patient you suspect...

Question 17

In familial hypercholesterolemia, cholesterol is deposited in various tissues because of the high concentration of LDL cholesterol in the plasma. Of particular concern is the oxidation of the excess LDL to form oxidized LDL (oxLDL). The oxLDL is taken up by macrophages, which become engorged to form foam cells. Which statement best describes the formation of foam cells?

A) cholesterol cannot be extracted from macrophages by HDL
B) expression of the receptors for oxLDL is increased in the macrophages
C) LDL enters by pinocytosis to form foam cells
D) LDL receptors on peripheral cells are upregulated
E) there is increased synthesis of cholesterol in macrophages as a result

Accepted Answer

The answer of In familial hypercholesterolemia, cholesterol is deposited in...

Question 18

A patient presents with very high levels of serum cholesterol. After a series of tests, it is concluded that the patient has high circulating levels of LDL cholesterol, but has normal levels of the hepatic LDL receptor. Which of the following could best explain the observations in this patient?

A) hepatocytes from the patient are defective in the selective removal of cholesterol from the LDL complex
B) hepatocytes from the patient have decreased levels of acyl-CoA:cholesterol acyltransferase ratio
C) the absence of the enzyme lipoprotein lipase in the endothelial cells of the liver
D) the patient has a mutated form of apoB-100
E) there is an altered level of phosphorylation of the LDL receptor

Accepted Answer

The answer of A patient presents with very high levels...

Question 19

A patient presents in your office with very high levels of serum cholesterol. He states that he has tried to follow the diet and exercise regimen you gave him last year. You decide that this patient would benefit by taking a drug of the statin class. This class of drug is effective in treating hypercholesterolemia because it has which of the following effects?

A) binds cholesterol, preventing it from being absorbed by the intestine
B) decreases the stability of HMG-CoA reductase
C) directly prevents the deposition of cholesterol on artery walls
D) inhibits the enzyme HMG-CoA reductase
E) stimulates phosphorylation of HMG-CoA reductase

Accepted Answer

The answer of A patient presents in your office with...

Question 20

Free cholesterol can affect cholesterol metabolism in the body by inhibiting cholesterol biosynthesis. Which of the following most closely reflects the mechanism by which cholesterol suppresses its own synthesis?

A) condensation of acetyl-CoA and acetoacetylCoA to form hydroxymethyl glutaryl-CoA
B) cyclizing of squalene to form lanosterol
C) formation of mevalonate from hydroxymethyl glutaryl-CoA
D) kinase that phosphorylates hydroxymethyl glutaryl-CoA reductase
E) reduction of 7-dehydrocholesterol to form cholesterol

Accepted Answer

The answer of Free cholesterol can affect cholesterol metabolism in...

Question 21

Which of the following vitamins can be used in high doses to treat hypercholesterolemia?&#10;A) folic acid&#10;B) niacin&#10;C) pyridoxine&#10;D) riboflavin&#10;E) thiamine

Accepted Answer

The answer of Which of the following vitamins can be...

Question 22

A 65-year-old woman is brought to the emergency room by her husband because she is experiencing chest pain radiating to her left arm. The attending physician diagnoses her as suffering from a mild myocardial infarction and prescribes appropriate intervention. Blood work reveals her total cholesterol to be 280 mg/dL, so a statin is prescribed. Statin drugs inhibit the activity of HMG-CoA reductase. Which of the following best describes how taking statin drugs leads to reduced serum cholesterol and LDL levels?

A) it decreases the serum level of LDL by promoting catabolism
B) it increases the serum level of HDL, thereby promoting increased reverse cholesterol transport
C) it inhibits synthesis of LDL receptors
D) it inhibits the formation of LDL from IDL
E) it inhibits the rate-limiting step in cholesterol biosynthesis

Accepted Answer

The answer of A 65-year-old woman is brought to the...

Question 23

A 35-year-old woman presents with crushing substernal chest pain and shortness of breath. A coronary artery is occluded due to an atherosclerotic plaque, and she is diagnosed with having a myocardial infarction. Her serum cholesterol level is 700 mg/dL. She has a family history of hypercholesterolemia. Which of the following is the inherited defect in individuals with familial hypercholesterolemia?

A) abnormal LDL receptors
B) high activity of HMG-CoA reductase
C) increased conversion of VLDL to LDL
D) low activity of 7-a hydroxylase
E) reduced plasma concentration of HDL

Accepted Answer

The answer of A 35-year-old woman presents with crushing substernal...

Question 24

Which of the following compounds directly inhibits the expression of the HMG-CoA reductase gene?&#10;A) cholesterol&#10;B) HMG-CoA&#10;C) isopentenyl pyrophosphate&#10;D) lanosterol&#10;E) squalene

Accepted Answer

The answer of Which of the following compounds directly inhibits...

Question 25

A 23-year-old woman presents with low red blood cell count, corneal opacities, and renal insufficiency. She is diagnosed with lecithin:cholesterol acyltransferase (LCAT) ratio deficiency. In which of the following reactions LCAT is involved?

A) converting cholesterol to cholesterol esters
B) hydrolysis of HDL
C) promoting uptake of HDL into liver cells
D) transfer of cholesterol esters from HDL to VLDL
E) uptake of cholesterol from liver cells

Accepted Answer

The answer of A 23-year-old woman presents with low red...

Question 26

An autopsy is conducted on a stillborn female fetus exhibiting multiple lethal congenital malformations and osteosclerosis. Analysis of lipids accumulated in tissues showed high levels of desmosterol and extremely low levels of cholesterol. Given the skeletal malformations and the lipid profiles obtained from this fetus, the pathologist makes a diagnosis of desmosterolosis. Which of the following enzymes was most likely defective in this fetus resulting in the lethality?

A) 7-dehydrocholesterol reductase
B) 24-dehydrocholesterol reductase
C) HMG-CoA reductase
D) mevalonate kinase
E) squalene monooxygenase

Accepted Answer

The answer of An autopsy is conducted on a stillborn...

Deck 26: Lipids: Cholesterol Metabolism