KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Part I ● Biochemistry

3-hydroxy-3-methylglutaryl (HMG)-CoA reductase on the smooth endoplasmic reticulum (SER) is the rate-limiting enzyme. Insulin activates the enzyme (dephosphorylation), and glucagon inhibits it. Mevalonate is the product, and the statin drugs competitively inhibit the enzyme. Cholesterol represses the expression of the HMG-CoA reductase gene and also increases degradation of the enzyme.

Farnesyl pyrophosphate, an intermediate in the pathway, may also be used for:

•Synthesis of CoQ for the mitochondrial electron transport chain

•Synthesis of dolichol pyrophosphate, a required cofactor in N-linked glycosylation of proteins in the endoplasmic reticulum

•Prenylation of proteins (a posttranslational modification) that need to be held in the cell membrane by a lipid tail. An example is the p21ras G protein in the insulin and growth factor pathways.

Hypercholesterolemia

A 55-year-old man went to see his physician for his annual checkup. Over the past 5 years, his bloodwork consistently showed that his total cholesterol was slightly high (205–220 mg/dL), HDL 45–50 mg/dL, and LDL 145 mg/dL. Serum C-reactive protein (CRP) value was always within normal range. Despite considerable efforts to lower his total cholesterol and LDL (exercise, 1 glass of wine per day, and a carefully controlled diet), his blood cholesterol values did not significantly change. No other problems were evident. He recently heard that the ideal blood level of LDL should be <100 mg/ dL. His physician decided to prescribe a statin drug. Within several weeks of taking the statin, the patient experienced more than usual muscle soreness, pain, and weakness when he exercised. He also noticed that his urine was red-brown.

For a large majority of people, statin drugs work efficiently and without side effects. Maximum lowering of blood cholesterol takes about 4–6 weeks. Because the liver is the site of most cholesterol synthesis, LFTs should be measured 2–3 months after starting the statin regimen. One consequence of statins inhibiting HMG-CoA reductase is the lessening of the downstream synthesis of CoQ, which is needed for the electron transport chain. Without properly functioning mitochondria, muscle would have a decreased ability to generate ATP required for muscle contraction. The red-brown urine is caused by the spillage of myoglobin from damaged muscle cells. CRP is a liver protein that is secreted in inflammation. There is a direct correlation between elevated CRP and atherosclerosis.

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Chapter 15 ● Lipid Synthesis and Storage

Review Questions

Select the ONE best answer.

1. What is the most positive activator of the process shown below?

8 Acetyl-CoA + n ATP + 14 NADPH → palmitate + 8 CoASH + nADP + nPi + 14 NADP

A.Acetyl-CoA

B.Citrate

C.Malonyl-CoA

D.Malate

E.Oxaloacetate

2.When adipose tissue stores triglyceride arriving from the liver or intestine, glycolysis must also occur in the adipocyte. Which of the following products or intermediates of glycolysis is required for fat storage?

A.Glycerol

B.Glucose 6-phosphate

C.Pyruvate

D.Acetyl-CoA

E.Dihydroxyacetone phosphate

Items 3 and 4

Abetalipoproteinemia is a genetic disorder characterized by malabsorption of dietary lipid, steatorrhea (fatty stools), accumulation of intestinal triglyceride, and hypolipoproteinemia.

3.A deficiency in the production of which apoprotein would most likely account for this clinical presentation?

A.ApoB-100

B.ApoB-48

C.ApoC-II

D.ApoA-I

E.ApoE

4.Patients with abetalipoproteinemia exhibit membrane abnormalities in their erythrocytes with production of acanthocytes (thorny-appearing cells). This unusual red cell morphology would most likely result from malabsorption of

A.palmitic acid

B.ascorbic acid

C.arachidonic acid

D.folic acid

E.linoleic acid

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Part I ● Biochemistry

5.A patient with a history of recurring attacks of pancreatitis, eruptive xanthomas, and increased plasma triglyceride levels (2,000 mg/dl) associated with chylomicrons, most likely has a deficiency in

A.lipoprotein lipase

B.LDL receptors

C.HMG-CoA reductase

D.apoB-48

E.apoB-100 receptor

6.Uncontrolled phagocytosis of oxidized LDL particles is a major stimulus for the development of foam cells and fatty streaks in the vascular subendothelium. This process may be inhibited by increased dietary intake of

A.vitamin E

B.vitamin B6

C.vitamin D

D.vitamin B12

E.vitamin K

Items 7–9

A 42-year-old man presents with a chief complaint of intermittent claudication during exercise. His family history is significant for the presence of cardiovascular disease on his father’s side, but not on his mother’s side. Physical exam reveals xanthelasmas and bilateral tendon xanthomas. A plasma lipid profile reveals cholesterol level 340 mg/dL, with a high LDL/HDL ratio. He is given instructions for dietary modifications and a prescription for simvastatin.

7.The clinical findings noted in this patient are most likely caused by deficient production of

A.lethicin cholesterol acyltransferase

B.apoB-100 receptors

C.fatty acyl-CoA synthetase

D.VLDL from LDL

E.cholesterol ester transfer protein

8.The anticholesterolemic action of simvastatin is based on its effectiveness as a competitive inhibitor of the rate-limiting enzyme in cholesterol biosynthesis. The reaction product normally produced by this enzyme is

A.squalene

B.methylmalonate

C.lanosterol

D.mevalonate

E.acetoacetate

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Chapter 15 ● Lipid Synthesis and Storage

9.From a Lineweaver-Burk plot, the Km and Vmax of this rate-limiting enzyme were calculated to be 4 10-3 M and 8 102 mmol/h, respectively. If the given experiment is repeated in the presence of simvastatin, which of the following values would be obtained?

10.A 20-year-old man is taken to the university clinic to determine the cause of recurring hyperlipidemia, proteinuria, and anemia. Fasting blood tests reveal slightly elevated concentrations of unesterified cholesterol and phosphatidylcholine. The patient is given a 100 gram chocolate bar and blood lipid levels are monitored hourly. Results reveal significantly increased levels of unesterified cholesterol and phosphatidylcholine for extended periods. Deficiency of which of the following proteins is most likely to be associated with these observations?

A.Acyl-CoA:cholesterol acyltransferase (ACAT)

B.Apoprotein A-1

C.Apoprotein B48

D.Apoprotein B100

E.Lipoprotein lipase

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Part I ● Biochemistry

Answers

1.Answer: B. Citrate is a potent activator of acetyl-CoA carboxylase for fatty acid synthesis.

2.Answer: E. To reform triglycerides from the incoming fatty acids, glycerol 3-P must be available. The adipose can produce this only from DHAP in glycolysis.

3.Answer: B. ApoB-48 is required for intestinal absorption of dietary fat in the form of chylomicrons. ApoB-100 formation is also impaired in these patients, but this would not explain the clinical symptoms described.

4.Answer: E. The genetic defect would result in malabsorption of the 3 fatty acids listed, but only linoleate is strictly essential in the diet. Absorption of water-soluble ascorbate and folate would not be significantly affected.

5.Answer: A. These are the clinical features of lipoprotein lipase deficiency (type I lipoproteinemia). LDL receptor defects would result in elevated LDLs. HMG-CoA reductase and ApoB-100 have no direct relationship to chylomicrons. ApoB-48 deficiency would result in decreased production of chylomicrons.

6.Answer: A. Only vitamin E is an antioxidant.

7.Answer: B. The findings are indicative of heterozygous type lla familial hypercholesterolemia, an autosomal dominant disease. Deficient CETP, LCAT or fatty acid-CoA synthetase would not elevate LDL cholesterol. VLDL are not produced from LDL.

8.Answer: D. Must know that mevalonate precedes squalene and lanosterol in the pathway, and that methylmalonate and acetoacetate are not associated with cholesterolgenesis.

9.Answer: D. With a competitive inhibitor, there will be an increase in Km with no change in Vmax. Choice A would be for a noncompetitive inhibitor (Vmax decreased, Km unaltered).

10.Answer: B. Apo A-1 is present on the surface of HDL and functions to activate circulating LCAT (lecithin:cholesterol acyltransferase) to esterify cholesterol,usinglecithin(phosphatidylcholine)asthefattyaciddonor.Esterification of cholesterol in blood occurs to trap the resultant cholesterol esters in HDL where they can subsequently be transferred to other lipoproteins (IDL) or taken up directly by hepatocytes and steroidogenic tissues.

Deficiencies of apoprotein B100 and apoprotein B48 (choices D and C) result in abetalipoproteinemia characterized by decreased blood triglycerides and cholesterol.

ACAT (choice A) is an intracellular enzyme and esterifies cholesterol inside cells, but not in blood.

Deficiency of LPL (choice E) would result in type 1 hyperlipidemia and is characterized by elevated serum triglycerides.

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