Ebook BRS Biochemistry, molecular biology and genetics (5th edition): Part 1

(BQ) Part 1 book BRS Biochemistry, molecular biology and genetics presents the following contents: Organic chemistry review; protein structure and function; enzymes, biochemistry of digestion; glycolysis; the tricarboxylic acid cycle, electron transport chain, and oxidative metabolism; glycogen metabolism; gluconeogenesis and the maintenance of blood glucose levels,... and other contents.

Biochemistry, Molecular Biology, and Genetics Todd A Swanson, M.D., Ph.D Resident in Radiation Oncology William Beaumont Hospital Royal Oak, Michigan Sandra I Kim, M.D., Ph.D Division of Nuclear Medicine and Molecular Imaging Massachusetts General Hospital Boston, Massachusetts Marc J Glucksman, Ph.D Professor, Department of Biochemistry and Molecular Biology Director, Midwest Proteome Center Rosalind Franklin University of Medicine and Science The Chicago Medical School North Chicago, Illinois WITH EDITORIAL CONSULTATION BY Michael A Lieberman, Ph.D Dean, Instructional and Research Computing, UCit Distinguished Teaching Professor University of Cincinnati Cincinnati, OH Acquisitions Editor: Charles W Mitchell Product Manager: Stacey L Sebring Marketing Manager: Jennifer Kuklinski Designer: Holly Reid McLaughlin Compositor: Cadmus Communications Printer: C & C Offset Printing Copyright  C 2010 Lippincott Williams & Wilkins 351 West Camden Street Baltimore, MD 21201 530 Walnut Street Philadelphia, PA 19106 All rights reserved This book is protected by copyright No part of this book may be reproduced in any form or by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner The publisher is not responsible (as a matter of product liability, negligence, or otherwise) for any injury resulting from any material contained herein This publication contains information relating to general principles of medical care that should not be construed as specific instructions for individual patients Manufacturers’ product information and package inserts should be reviewed for current information, including contraindications, dosages, and precautions Printed in Hong Kong First Edition, 1990 Second Edition, 1994 Third Edition, 1999 Fourth Edition, 2007 Library of Congress Cataloging-in-Publication Data Swanson, Todd A Biochemistry, molecular biology, and genetics / Todd A Swanson, Sandra I Kim, Marc J Glucksman ; with editorial consultation by Michael A Lieberman — 5th ed p ;cm — (Board review series) Rev ed of: Biochemistry and molecular biology / Todd A Swanson, Sandra I Kim, Marc J Glucksman 4th ed c2007 Includes bibliographical references and index ISBN 978-0-7817-9875-4 (hardcopy : alk paper) Biochemistry—Examinations, questions, etc Molecular biology—Examinations, questions, etc I Kim, Sandra I II Glucksman, Marc J III Lieberman, Michael, 1950- IV Swanson, Todd A Biochemistry and molecular biology V Title VI Series: Board review series [DNLM: Biochemical Phenomena—Examination Questions Biochemical Phenomena—Outlines Genetic Processes—Examination Questions Genetic Processes—Outlines QU 18.2 S972b 2010] QP518.3.S93 2010 572.8076—dc22 2009029693 The publishers have made every effort to trace the copyright holders for borrowed material If they have inadvertently overlooked any, they will be pleased to make the necessary arrangements at the first opportunity To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320 International customers should call (301) 223-2300 Visit Lippincott Williams & Wilkins on the Internet: http://www.LWW.com Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to 6:00 pm, EST For Olga, Maxwell, Anneliese, and the eagerly awaited new addition to the Swanson clan If not for you, all my efforts would be in vain Preface This revision of BRS Biochemistry, Molecular Biology, and Genetics includes additional high-yield material to help the reader master clinical principles of medical biochemistry as they prepare for the revamped Step USMLE Our goal is to offer a review book that both lays the foundations of biochemistry and introduces clinically relevant correlates In doing so, we have de-emphasized some of the rote memorization of structures and formulas that often obscure the big picture of medical biochemistry Clinical Correlates in each chapter provide additional clinical insight, distilling numerous clinical correlations into a format that offers the highest yield in review We hope that these correlations will help answer a commonly asked question: ‘‘Why we have to know this for the boards?’’ This revised edition also includes a new chapter on genetics as related to medical biochemistry We hope this chapter will augment other review texts on genetics that students may consult in preparation for Step Many of the questions at the end of each chapter have been revised to maximize their value for the student preparing for the exam A comprehensive exam at the end of this volume reinforces the concepts of the text Our objective has been to provide the student with clinically relevant questions in a format similar to that encountered on the USMLE Step Boards The breadth of questions is one of the many features of Lippincott’s Board Review Series titles We hope that the new edition of BRS Biochemistry, Molecular Biology, and Genetics becomes a valuable tool for students seeking high-yield resources as they prepare for the USMLE Step We recognize the changing nature of science and medicine, however, and encourage readers to send suggestions for improvement for this text or for our companion flash cards, to us via e-mail at LWW.com Todd Swanson Sandra Kim Marc Glucksman v Publisher’s Preface The Publisher acknowledges the editorial consultation of Michael A Lieberman, Ph.D., to this fifth edition In addition to his role as editorial consultant on every chapter, Dr Lieberman reviewed the entire manuscript to help ensure the accuracy, consistency, and timeliness of its content vii 148 Biochemistry, Molecular Biology, and Genetics diagnosed with anorexia nervosa In this patient, breakdown of fatty acids is required to provide energy Before being oxidized, fatty acids are activated in the cytosol to form which of the following? (A) (B) (C) (D) (E) ATP CoA Fatty acyl CoA Carnitine Malonyl CoA After surgical resection of part of her small intestine, a 40-year-old woman presents with chronic foul-smelling diarrhea and weight loss She is diagnosed with short bowel syndrome In this syndrome, fat cannot be properly absorbed, so long-chain fatty acids are mobilized from adipose tissue to generate energy for cell survival The initiating substrate for fatty acid oxidation is which of the following? (A) (B) (C) (D) (E) Long-chain fatty acid Fatty acyl carnitine Fatty acyl CoA b-Hydroxyacyl CoA Acetyl CoA An infant is born with a high forehead, abnormal eye folds, and deformed ear lobes and shows little muscle tone and movement After multiple tests, he is diagnosed with Zellweger syndrome, a disorder caused by peroxisome malformation What type of fatty acid would you expect to accumulate in patients with Zellweger syndrome? (A) (B) (C) (D) (E) Short-chain fatty acids Acetyl CoA Dicarboxylic acids Long-chain fatty acids Very-long-chain fatty acids A 4-month-old infant presents with a seizure His mother reports that her infant has been irritable and lethargic over the past several days The infant is found to be profoundly hypoglycemic and have low ketones Short-chain dicarboxylic acids are found to be elevated in the serum The most likely enzyme deficiency is which of the following? (A) Medium-chain acyl CoA dehydrogenase (B) (C) (D) (E) (MCAD) Carnitine acyltransferase I Hormone-sensitive lipase Pyruvate carboxylase Fatty acyl CoA synthetase 10 A 12-year-old Jamaican boy presents with intractable vomiting, abdominal pain, and lethargy and is profoundly hypoglycemic His symptoms are caused by Jamaican vomiting syndrome, a sickness caused by ingestion of hypoglycin, which is present in unripe ackee fruit Hypoglycin is metabolized to a form of nonmetabolizable carnitine, which interferes with normal fatty acid oxidation What is the primary role of carnitine? (A) Activates long-chain fatty acids in the cytosol (B) Transport of acyl groups across the inner mitochondrial membrane (C) Is converted to enoyl CoA (D) Is converted to b-hydroxyacyl CoA (E) Is involved in breakdown of even-chain, but not odd-chain, fatty acids Answers and Explanations The answer is C Triacylglycerol is formed when a diacylglycerol reacts with a fatty acyl CoA Glycerol and glycerol 3-phosphate form the backbone of the triacylglycerol Acetyl CoA and malonyl CoA are involved in fatty acid synthesis, and not directly in triacylglycerol synthesis The answer is A Intestinal epithelial cells are the site of chylomicron formation Dietary triacylglycerols are bound to apoproteins and other lipids to form the chylomicrons In the liver, triacylglycerols are incorporated into VLDLs, which enter the blood Triacylglycerols are stored in adipose tissue The muscle, heart, and adipose cells not package triacylglycerol into particles for export into the circulation The answer is A The thoracic duct carries lymph and triglyceride from the enteric circulation to the venous system Chylothorax is the accumulation of chylous fluid from a compromised thoracic duct Nontraumatic causes (e.g., malignant erosion) or traumatic causes (e.g., blunt trauma, cardiothoracic surgery) result in the slow accumulation of a milky fluid rich in triglycerides in the chest cavity Treatment is medical (somatostatin in children) and surgical (percutaneous drainage or thoracostomy tube drainage) Triglyceride is primarily stored in the adipose cells Intestinal cells not produce triglyceride from glucose; these cells pass glucose directly into the circulation VLDL is produced by the liver, not adipose tissue The answer is D The primary source of carbons for fatty acid synthesis is dietary carbohydrate Fatty acids are synthesized from acetyl CoA in the hepatocyte cytosol, and esterification to glycerol to form triacylglycerols also occurs primarily in the liver The fatty acyl chain on the fatty acid synthase complex is elongated two carbons at a time With each two-carbon addition to the elongating chain, the b-keto group is reduced in a reaction that requires NADPH NADPH is a reducing equivalent produced by the pentose phosphate pathway and the malic enzyme NADP+ is a product of fatty acid biosynthesis, not a substrate The answer is B Linoleate and a-linolenate are the essential fatty acids required in the human diet Palmitate (C16:0) is synthesized by the fatty acid synthase complex Phosphatidic acid is an intermediate in triacylglycerol synthesis, which is formed using glycerol as a precursor in the liver and using glucose as a precursor in adipose tissue It can be synthesized without the need for an essential fatty acid The answer is C Long-chain fatty acids are activated, in a reaction requiring ATP and CoA, to a fatty acyl CoA Carnitine reacts with fatty acyl CoA, forming fatty acyl carnitine, in order to transport the fatty acid across the mitochondrial membrane Malonyl CoA is an intermediate in fatty acid synthesis The answer is C Fatty acyl CoA undergoes b-oxidation in a spiral involving four steps Longchain fatty acids are released from adipose cells and must be activated and transported into mitochondria for oxidation Fatty acyl CoA reacts with carnitine, forming fatty acyl carnitine, which crosses the inner mitochondrial membrane The acyl group is then transferred back to CoA, forming fatty acyl CoA in the mitochondrial matrix Subsequent reactions convert the fatty acyl CoA to trans2 fatty enoyl CoA, b-hydroxy acyl CoA, and keto acyl CoA The end product of fatty acid oxidation is acetyl CoA, which is oxidized via the TCA cycle and oxidative phosphorylation to produce carbon dioxide, water, and ATP The answer is E Very-long-chain fatty acids are initially oxidized in peroxisomes, generating hydrogen peroxide, NADH, and acetyl CoA Once the fatty acids have been shortened to about to 10 carbons in length, they are transferred to the mitochondria to finish their oxidation via traditional b-oxidation Thus, very-long-chain fatty acids will accumulate with this peroxisomal disorder Short-chain and long-chain fatty acids are oxidized within the mitochondria via b-oxidation Acetyl CoA will not accumulate with a peroxisomal disorder because it will also be 149 150 Biochemistry, Molecular Biology, and Genetics oxidized in the mitochondria Dicarboxylic acids accumulate when there is a defect in mitochondrial b-oxidation, and o-oxidation begins to play a larger role in generating energy The answer is A The infant has MCAD deficiency The child can only partially oxidize fatty acids (to the 6- to 10-carbon stage), leading to reduced energy generation and low acetyl CoA levels The low acetyl CoA reduces gluconeogenesis because pyruvate carboxylase cannot be fully activated The reduced energy also contributes to the reduced levels of gluconeogenesis because that pathway requires energy to proceed The dicarboxylic acids result from o-oxidation of the medium-chain acyl CoAs, to try and generate more energy Defects in CAT I or hormonesensitive lipase would result in a complete lack of fatty acid oxidation, and the dicarboxylic acids would not be observed A defect in pyruvate carboxylase, although negatively affecting gluconeogenesis, would not affect fatty acid oxidation 10 The answer is B In the outer mitochondrial membrane, carnitine reacts with fatty acyl CoA to form fatty acyl carnitine, which can then pass to the inner mitochondrial membrane Therefore, carnitine is important for the transport of fatty acyl CoA from the cytosol to the mitochondria and allow for b-oxidation to occur Carnitine is not involved in activation of fatty acids or b-oxidation itself (which eliminates answer choices A, C, D, and E) As a note of interest, hypoglycin leads to inhibition of gluconeogenesis (due to a lack of fatty acid oxidation, leading to low ATP and acetyl CoA levels) Profound hypoglycemia results, which is how hypoglycin was named chapter 10 Cholesterol Metabolism and Blood Lipoproteins I CHOLESTEROL AND BILE SALT METABOLISM A Cholesterol is synthesized from cytosolic acetyl coenzyme A (CoA) by a sequence of reactions (Figure 10-1) Glucose is a major source of carbon for acetyl CoA Acetyl CoA is produced from glucose by the same sequence of reactions used to produce cytosolic acetyl CoA for fatty acid biosynthesis (Figure 10-2) Cytosolic acetyl CoA forms acetoacetyl CoA, which condenses with another acetyl CoA to form hydroxymethylglutaryl CoA (HMG-CoA) (Figure 10-1) Acetyl CoA undergoes similar reactions in the mitochondrion, where HMG-CoA is used for ketone body synthesis Cytosolic HMG-CoA, a key intermediate in cholesterol biosynthesis, is reduced in the endoplasmic reticulum to mevalonic acid by the regulatory enzyme HMG-CoA reductase a HMG-CoA reductase is inhibited by cholesterol b HMG-CoA reductase is also inhibited by phosphorylation by the adenosine monophosphate (AMP)-activated protein kinase c In the liver, HMG-CoA reductase is also inhibited by bile salts and is induced when blood insulin levels are elevated CLINICAL CORRELATES Statins are medications that function as competitive inhibitors of HMG-CoA reductase, thus reducing the serum level of cholesterol Statins have been effective in regulating circulating cholesterol levels in patients with hypercholesterolemia Mevalonic acid is phosphorylated and decarboxylated to form the five-carbon (C-5) isoprenoid, isopentenyl pyrophosphate (Figure 10-1) Two isopentenyl pyrophosphate units condense, forming a C-10 compound, geranyl pyrophosphate, which reacts with another C-5 unit to form a C-15 compound, farnesyl pyrophosphate (Figure 10-1) Squalene is formed from two C-15 units and then oxidized and cyclized, forming lanosterol (Figure 10-1) Lanosterol is converted to cholesterol in a series of steps (Figure 10-1) The ring structure of cholesterol cannot be degraded in the body The bile salts in the feces are the major form in which the steroid nucleus is excreted CLINICAL CORRELATES Gallstones can be made of cholesterol Ursodeoxycholate is a medication used to inhibit the formation of cholesterol gallstones This medication is a hydrophilic bile salt that decreases the content of cholesterol in bile B Bile salts are synthesized in the liver from cholesterol (Figure 10-3) An a-hydroxyl group is added to carbon of cholesterol A 7a-hydroxylase, which is inhibited by bile salts, catalyzes this rate-limiting step 151 152 Biochemistry, Molecular Biology, and Genetics FIGURE 10-1 Cholesterol biosynthesis HMG-CoA, hydroxymethylglutaryl coenzyme A; €, inhibited by; P phosphate CLINICAL CORRELATES Atherosclerosis is the buildup of lipid-rich plaques in the intima layer of arteries Blood clots can form on these lipid-rich plaques, or part of the plaque may suddenly break loose, occluding a coronary or cerebral artery Occlusion of a coronary artery can cause a myocardial infarct (heart attack), and occlusion of a cerebral artery can cause an ischemic cerebrovascular accident (stroke) The double bond of cholesterol is reduced, and further hydroxylations occur, resulting in two compounds One has a-hydroxyl groups at positions and 7; and the other has a-hydroxyl groups at positions 3, 7, and 12 The side chain is oxidized and converted to a branched, five-carbon chain, containing a carboxylic acid at the end a The bile acid with hydroxyl groups at positions and is chenocholic acid The bile acid with hydroxyl groups at positions 3, 7, and 12 is cholic acid b These bile acids each have a pK of about (1) Above pH 6, the molecules are salts (i.e., they ionize and carry a negative charge) Chapter 10 Cholesterol Metabolism and Blood Lipoproteins 153 Glucose Glucose Liver NADP+ G–6–P Pentose–P pathway Glycolysis F–6–P TG Glycerol–3–P FACoA ApoB–100 Other lipids F–1,6–BP Palmitate Glyceraldehyde–3–P DHAP Pyruvate VLDL NADPH fatty acid synthase NADP+ Blood Malate Malonyl CoA Pyruvate OAA Acetyl CoA Citrate OAA Acetyl CoA Citrate FIGURE 10-2 Synthesis of fatty acids and triaglycerols from glucose DHAP, dihydroxyacetone phosphate; F-6-P, fructose 6-phosphate; F-1,6-BP, fructose 1,6-biphosphate; G-6-P, glucose 6-phosphate; OAA, oxaloacetate; VLDL, very-low-density lipoprotein (2) At pH (the pH in the intestinal lumen), half of the molecules are ionized and carry a negative charge (3) Below pH 6, the molecules become protonated, and their charge decreases as the pH is lowered Conjugation of the bile salts (Figure 10-3, middle) a The bile salts are activated by adenosine triphosphate (ATP) and coenzyme A, forming their CoA derivatives, which can form conjugates with either glycine or taurine b Glycine, an amino acid, forms an amide with the carboxyl group of a bile salt, forming gly- cocholic acid or glycochenocholic acid (1) These bile salts each have a pK of about (2) This pK is lower than the unconjugated bile salts, so the conjugated bile salts are more completely ionized at pH in the gut lumen and serve as better detergents c Taurine, which is derived from the amino acid cysteine, forms an amide with the carboxyl group of a bile salt (1) Because of the sulfite group on the taurine moiety, the taurocholic and taurochenocholic acids have a pK of about (2) They ionize very readily in the gut and are the best detergents among the bile salts Fate of the bile salts (Figure 10-3, bottom) a Cholic acid, chenocholic acid, and their conjugates are known as the primary bile salts They are made in the liver and secreted via the bile through the gallbladder into the intestine, where, because they are amphipathic (contain both hydrophobic and hydrophilic regions), they aid in lipid digestion 154 Biochemistry, Molecular Biology, and Genetics hydroxyls to α FIGURE 10-3 Synthesis and fate of bile salts CoASH, nonreacted coenzyme A b In the intestine, bile salts can be deconjugated and dehydroxylated (at position 7) by intesti- nal bacteria c Bile salts are resorbed in the ileum and return to the liver, where they can be reconjugated with glycine or taurine However, they are not rehydroxylated Those that lack the 7ahydroxyl group are called secondary bile salts d The liver recycles about 95% of the bile salts each day; 5% are lost in the feces CLINICAL CORRELATES Bile acid sequestrants, such as cholestyramine, bind with bile acids in the intestinal lumen The insoluble complex of bile acid sequestrant and bile acid is eliminated in the stool This causes fecal loss of cholesterol As the body loses dietary cholesterol, the cells take up low-density lipoprotein (LDL) from circulation, which results in a lowering of circulating cholesterol C Steroid hormones are synthesized from cholesterol, and 1,25-dihydroxycholecalciferol (active vitamin D3) is synthesized from a precursor of cholesterol Chapter 10 Cholesterol Metabolism and Blood Lipoproteins 155 II BLOOD LIPOPROTEINS A Composition of the blood lipoproteins (Table 10-1) The major components of lipoproteins are triacylglycerols, cholesterol, cholesterol esters, phospholipids, and proteins The protein components (called apoproteins) are designated A, B, C, and E Chylomicrons are the least dense of the blood lipoproteins because they have the most triacylglycerol and the least protein Very-low-density lipoprotein (VLDL) is more dense than chylomicrons but still has a high content of triacylglycerol Intermediate-density lipoprotein (IDL), which is derived from VLDL, is denser than VLDL and has less than half the amount of triacylglycerol of VLDL LDL has less triacylglycerol than IDL and more protein and, therefore, is denser than the IDL from which it is derived LDL has the highest content of cholesterol and its esters High-density lipoprotein (HDL) is the densest lipoprotein It has the lowest triacylglycerol content and the highest protein content of all the lipoprotein particles B Metabolism of chylomicrons (Figure 10-4) Chylomicrons are synthesized in intestinal epithelial cells Their triacylglycerols are derived from dietary lipid, and their major apoprotein (apo) is apo B-48 Chylomicrons travel through the lymph into the blood (Step 1) Apo C-II, the activator of lipoprotein lipase, and apo E are transferred to nascent chylomicrons from HDL, and mature chylomicrons are formed (Step 2) In peripheral tissues, particularly adipose and muscle, the triacylglycerols are digested by lipoprotein lipase As the chylomicron loses triacylglycerol, a chylomicron remnant is formed The chylomicron remnants interact with receptors on liver cells and are taken up by endocytosis The contents are degraded by lysosomal enzymes, and the products (amino acids, fatty acids, glycerol, cholesterol, and phosphate) are released into the cytosol and reused C Metabolism of VLDL (Figure 10-4) VLDL is synthesized in the liver, particularly after a high-carbohydrate meal It is formed from triacylglycerols that are packaged with cholesterol, apoproteins (particularly apo B-100), and phospholipids, and it is released into the blood (Step 3) In peripheral tissues, particularly adipose and muscle, VLDL triacylglycerols are digested by lipoprotein lipase, and VLDL is converted to IDL CLINICAL CORRELATES The agent gemfibrozil, a member of the fibrate class of lipid-lowering agents, activates the transcription of lipoprotein lipase by activating the PPAR (peroxisome proliferator-activated receptors) family of receptors Therefore, the drug decreases the level of VLDLs and other triglyceride-rich lipoproteins t a b l e 10-1 Component Composition of the Blood Lipoproteins Chylomicrons VLDL IDL LDL HDL Triacylglycerol Protein Apolipoprotein type Cholesterol Cholesterol ester 85% 2% B, C, E 1% 2% 55% 9% B, C, E 7% 10% 26% 11% B, E 8% 30% 10% 20% B 10% 35% 8% 45% A, C, E 5% 15% Phospholipid 8% 20% 23% 20% 25% HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein 156 Biochemistry, Molecular Biology, and Genetics FIGURE 10-4 Metabolism of chylomicrons and very-low-density lipoprotein (VLDL) C, cholesterol; FA, fatty acid; HTGL, hepatic triglyceride lipase; LPL, lipoprotein lipase; TG, triacylglycerol; TG , triacylglycerol of chylomicrons and VLDL; €, inhibits; È, stimulates; Œ to Ž, fate of chylomicrons; Ž to ‘, fate of VLDL IDL returns to the liver, is taken up by endocytosis, and is degraded by lysosomal enzymes (Step 4) IDL can also be further degraded, forming LDL (Step 5) LDL reacts with receptors on various cells, is taken up by endocytosis, and is digested by lysosomal enzymes (Step 6) a Cholesterol, released from cholesterol esters by a lysosomal esterase, can be used for the synthesis of cell membranes or for the synthesis of bile salts in the liver or steroid hormones in endocrine tissue b Cholesterol inhibits HMG-CoA reductase (a key enzyme in cholesterol biosynthesis) and, thus, decreases the rate of cholesterol synthesis by the cell c Cholesterol inhibits synthesis of LDL receptors (downregulation) and, thus, reduces the amount of cholesterol taken up by cells d Cholesterol activates acyl:cholesterol acyltransferase (ACAT), which converts cholesterol to cholesterol esters for storage in cells D Familial hypercholesterolemia (types I, IIa, IIb, III, IV, V) (Table10-2) E Metabolism of HDL (Figure 10-5) HDL is synthesized by the liver and released into the blood as small, disk-shaped particles The major protein of HDL is apo A Chapter 10 t a b l e 10-2 Cholesterol Metabolism and Blood Lipoproteins Hyperlipidemias Etiology of Lipid Disorder Disease Description Type I Hyperlipoproteinemia (rare genetic disorders) Type IIa Familial hypercholesterolemia (common autosomal dominant inheritance) Familial combined hyperlipoproteinemia (common autosomal dominant inheritance) Familial dysbetalipoproteinemia (rare) Familial hyperlipemia (common) Type IIb Type III Type IV Type V 157 Biochemical Finding Lipoprotein lipase deficiency or apo C-II deficiency LDL receptor deficiency Chylomicrons high Elevated LDL only Decreased LDL receptor and increased Apo B LDL and VLDL high and triglycerides < 1000 mg/dL Apo E defect Increased IDL (a VLDL remnant) Increased VLDLs VLDL overproduction along with decreased clearance Hypertriglyceridemia with chylomicronemia (uncommon) Increased VLDL production and decreased lipoprotein lipase production Chylomicrons and VLDL elevated HDL, high-density lipoprotein; IDL ¼ intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein CLINICAL CORRELATES Tangier disease is a disease of cholesterol transport The first case was identified in a patient who lived on the island of Tangier and who had characteristic orange-colored tonsils, a very low HDL level, and an enlarged liver and spleen Because of a mutation in a transport protein, cholesterol cannot properly exit the cell to bind to apo A (forming HDL) This results in a very low HDL level Liver Bile salts Lysosome action Blood ApoB-48 Nascent chylomicron HDL Cholesterol HDL ApoC II ApoA Glucose ApoB-48 ApoE ApoCII Chylomicron ApoE ApoB-100 Nascent VLDL LCAT ApoB-100 IDL ApoAI C CE HDL LDL CE TG VLDL PL CETP TG C PL C C C VLDL ApoCII ApoE Cell membrane C Cell FIGURE 10-5 High-density lipoprotein (HDL) function and metabolism Apo, apoprotein; C, cholesterol; CE, cholesterol ester; CETP, cholesterol ester transfer protein; IDL, intermediate-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; PL, phospholipid; TG, triacylglycerol; VLDL, very-low-density lipoprotein 158 Biochemistry, Molecular Biology, and Genetics Apo C-II, which is transferred by HDL to chylomicrons and VLDL, serves as an activator of lipoprotein lipase a Apo E is also transferred and serves as a recognition factor for cell surface receptors b Apo C-II and apo E are transferred back to HDL after digestion of triacylglycerols of chylomicrons and VLDL Cholesterol, obtained by HDL from cell membranes or from other lipoproteins, is converted to cholesterol esters within the HDL particle by the lecithin:cholesterol acyltransferase (LCAT) reaction, which is activated by apo A-I a A fatty acid from position of lecithin (phosphatidylcholine), a component of HDL, forms an ester with the 3-hydroxyl group of cholesterol, producing lysolecithin and a cholesterol ester b As cholesterol esters accumulate in the core of the lipoprotein, HDL particles become spheroids CLINICAL CORRELATES LCAT deficiency results in an inability to convert cholesterol associated with HDL to cholesterol esters Ordinarily, these cholesterol esters would be transferred to other lipoproteins, which would then be taken up by receptors in the liver Therefore, by inducing esterification of cholesterol, LCAT is important for the continued removal of cholesterol from the periphery Clinical manifestations include defects in the kidneys, red blood cells, and the cornea of the eyes HDL transfers cholesterol esters to other lipoproteins in exchange for various lipids Cholesterol ester transfer protein (CETP) mediates this exchange VLDL and other lipoproteins carry the cholesterol esters back to the liver HDL particles and other lipoproteins are taken up by the liver by endocytosis and hydrolyzed by lysosomal enzymes Cholesterol, released from cholesterol esters, can be packaged by the liver in VLDL and released into the blood or converted to bile salts and secreted into the bile Review Test Directions: Each of the numbered questions or incomplete statements in this section is followed by answers or by completions of the statement Select the one lettered answer or completion that is best in each case Which of the following apoproteins is an acti- A 40-year-old man presents with chest pain vator of lipoprotein lipase? that radiates to his left jaw and shoulder He is diagnosed with a myocardial infarction and is prescribed a statin medication Statins are competitive inhibitors of HMG-CoA reductase, which converts HMG-CoA to which of the following? (A) (B) (C) (D) (E) Apo A Apo B Apo C-II Apo D Apo E The major carriers of triacylglycerols are which of the following? (A) (B) (C) (D) (E) Chylomicrons and VLDL IDL and LDL VLDL and LDL HDL and LDL Chylomicrons and LDL A 40-year-old Hispanic woman with a body mass index of 34 presents with acute right upper quadrant pain, nausea, and vomiting after eating a meal rich in lipids She is diagnosed with having cholelithiasis and is placed on a bile salt analog that is used to inhibit the formation of cholesterol gallstones Which of the following is an example of a bile salt? (A) (B) (C) (D) (E) HMG-CoA Mevalonate Squalene Lanosterol Chenocholic acid An 8-year-old boy presents with orangecolored tonsils, a very low HDL level, and an enlarged liver and spleen and is diagnosed with Tangier disease Which of the following statements best describes HDL? (A) It is produced in skeletal muscle (B) It scavenges cholesterol from cell membranes (C) Its major protein is apo E (D) It is formed when VLDL is digested by lipoprotein lipase (E) It activates ACAT (A) (B) (C) (D) (E) Mevalonate Isopentenyl pyrophosphate Geranyl pyrophosphate Farnesyl pyrophosphate Cholesterol A 45-year-old woman presents with oily, foul-smelling stool, which appears to be due to an obstruction of the bile duct Which of the following statements correctly describes bile salts? (A) They can act as detergents, aiding in lipid digestion (B) They are stored in the intestines (C) Ninety-five percent of bile salts are excreted in the feces, and 5% are recycled back to the liver (D) Bile salts are synthesized in the intestines (E) Squalene and lanosterol are examples of bile salts A 55-year-old woman presents with crushing substernal chest pain and shortness of breath A coronary artery is occluded owing to an atherosclerotic plaque, and a high myocardial infarct is diagnosed High serum HDL levels are protective against the development of atherosclerosis because HDL does which of the following? (A) (B) (C) (D) (E) Inhibits cholesterol production by the liver Inhibits HMG-CoA reductase Increases VLDL production Increases LDL production Brings cholesterol esters back to the liver A 30-year-old man presents with weakness in his right upper and lower extremities He is diagnosed with an acute middle cerebral artery stroke secondary to atherosclerosis Genetic 159 160 Biochemistry, Molecular Biology, and Genetics studies show that he has familial hypercholesterolemia, type II, a disorder caused by a deficiency of LDL receptors Which of the following statements best describes patients with type II familial hypercholesterolemia? (A) After LDL binds to the LDL receptor, the LDL is degraded extracellularly (A) Cellular HMG-CoA reductase activity is not inhibited (B) The triglycerides in chylomicrons cannot be degraded (C) The VLDL level in the serum increases (D) The HDL level in the serum increases (E) The VLDL cannot be converted to IDL (B) The number of LDL receptors on the sur- 10 A 25-year-old woman presents with a low face of hepatocytes increases (C) Cholesterol synthesis by hepatocytes increases (D) Excessive cholesterol is released by LDL (E) The cholesterol level in the serum decreases red blood cell count, corneal opacities, and kidney insufficiency She is diagnosed with LCAT deficiency LCAT is involved in which of the following processes? A 40-year-old woman presents with an LDL serum level of 400 (recommended level is