Clinical Lipidology: A Companion to Braunwald's Heart Disease

591 Pages·2008·38.74 MB·English

by  Christie M. Ballantyne MD

1600 John F. Kennedy Blvd.
Ste 1800
Philadelphia, PA 19103-2899
CLINICAL LIPIDOLOGY: A COMPANION TO BRAUNWALD’S
HEART DISEASE ISBN: 978-1-4160-5469-6
Copyright © 2009 by Saunders, an imprint of Elsevier Inc.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or
by any means, electronic or mechanical, including photocopying, recording, or any information
storage and retrieval system, without permission in writing from the publisher. Permissions may
be sought directly from Elsevier’s Rights Department: phone: [phone] (US) or (+44) 1865
843830 (UK); fax: [phone]; e-mail: [email protected]. You may also
complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions.
Notice
Knowledge and best practice in this fi eld are constantly changing. As new research and
experience broaden our knowledge, changes in practice, treatment and drug therapy may
become necessary or appropriate. Readers are advised to check the most current information
provided (i) on procedures featured or (ii) by the manufacturer of each product to be admin-
istered, to verify the recommended dose or formula, the method and duration of administra-
tion, and contraindications. It is the responsibility of the practitioner, relying on their own
experience and knowledge of the patient, to make diagnoses, to determine dosages and the
best treatment for each individual patient, and to take all appropriate safety precautions.
To the fullest extent of the law, neither the Publisher nor the Authors assume any liability
for any injury and/or damage to persons or property arising out of or related to any use of the
material contained in this book.
The Publisher
Library of Congress Cataloging-in-Publication Data
Clinical lipidology : a companion to Braunwald’s heart disease / [edited by] Christie M.
Ballantyne. — 1st ed.
p. ; cm.
ISBN 978-1-4160-5469-6
1. Lipids. 2. Lipoproteins. 3. Heart—Diseases. I. Ballantyne, Christie M. II.
Braunwald’s heart disease.
[DNLM: 1. Lipoproteins—metabolism. 2. Cardiovascular Diseases—complications. 3.
Dyslipidemias. 4. Lipid Metabolism. QY 465 C641 2009]
QP751.C55 2009
612.3’97—dc22
Executive Publisher: Natasha Andjelkovic
Editorial Assistant: Isabel Trudeau
Senior Project Manager: David Saltzberg
Design Direction: Steve Stave
Cover artwork provided by Peter Libby and Steven Lee
Printed in China
Last digit is the print number: 9 8 7 6 5 4 3 2 1
FM_i-xx-X5469.indd vi 10/7/08 10:44:11 AM
Acknowledgments
I would like to thank my family for their support during the writing of this book, since it meant time away from
them: My wife, Yasmine, and my daughers, Leyla, Christina, and Katina.
I would also like to thank the individuals who inspired me to pursue academic preventive cardiology: Donald
Seldin, who inspired me to teach; Jim Willerson, who was a role model for hard work and dedication to patient
care; Art Beaudet, for his rigorous approach to the scientifi c method and critical thinking; and Tony Gotto, who
was a role model as a clinician–scientist–educator–father–administrator.
I would also like to thank Kerrie Jara for her help in preparing this book.
vii
FM_i-xx-X5469.indd vii 10/7/08 10:44:11 AM
Contributing Authors
Gerd Assmann, M.D. Tina J. Chahil, M.D.
Institut for Klinische Chemie und Laboratoriumsmedizin, Columbia University College of Physicians and Surgeons,
Albert-Schweitzer, Munster, Germany Department of Medicine, Division of Preventive Medicine
and Nutrition, New York, New York
Deborah Bagshaw
The Pennsylvania State University, University Park, Timothy S. Church, M.D., MPH, Ph.D.
Pennsylvania Pennington Biomedical Research Center, Baton Rouge,
Louisiana
Ashok Balasubramanyam, M.D.
Professor of Medicine, Baylor College of Medicine, Houston, David E. Cohen, M.D., Ph.D.
Texas Director of Hepatology, Division of Gastroenterology Brigham
and Women’s Hospital, Harvard Medical School Director,
Christie M. Ballantyne, M.D. Harvard-MIT Division of Health Sciences and Technology;
Professor of Medicine, Chief, Section of Atherosclerosis and Associate Professor of Medicine and Health Sciences and
Vascular Medicine, Baylor College of Medicine, Houston, Technology, Harvard Medical School, Boston, Massachusetts
Texas
Michael H. Davidson, M.D., FACC
Philip Barter, M.D., Ph.D., FRACP The University of Chicago Pritzker School of Medicine,
The Heart Research Institute, Sydney, Australia Chicago, Illinois
Harold Bays, M.D., FACP Prakash C. Deedwania, M.D., FAHA, FACP, FACC
Louisville Metabolic and Atherosclerosis Research Center Veterans Administration Central California Healthcare System,
(L-MARC), Louisville, Kentucky University of California Fresno, Fresno, California
Roger S. Blumenthal, M.D., FACC Jean-Pierre Després, Ph.D., FAHA
Professor of Medicine, Director, The Johns Hopkins Centre de recherche de l’Hôpital Laval, Pennsylvaniavillon
Ciccarone Center for the Prevention of Heart Disease, Marguerite-D’Youville, Québec, Canada
Baltimore, Maryland
Sridevi Devaraj, Ph.D., DABCC
H. Bryan Brewer, Jr., M.D.
University of California Davis Medical Center, Sacramento,
Director, Washington Cardiovascular Associates; Senior
California
Research Consultant, Lipoprotein and Atherosclerosis
Research, Cardiovascular Research Institute, MedStar
Patrick J. Devine, M.D.
Research Institute, Washington, D.C.
Cardiology Service, Walter Reed Army Medical Center
Washington, D.C.
B. Greg Brown, M.D., Ph.D.
University of Washington, Department of Medicine, Seattle,
Zahi A. Fayad, Ph.D.
Washington
Mount Sinai School of Medicine, New York, New York
John D. Brunzell, M.D.
Professor Emeritus, Department of Medicine, Division of Sergio Fazio, M.D., Ph.D.
Metabolism, Endocrinology and Nutrition; Clinical Director, Vanderbilt University Medical Center, Nashville, Tennessee
Northwest Lipid Metabolism and Diabetes Research
Laboratories; University of Washington, Seattle, Washington Bengt Fellstrøm, M.D., Ph.D.
Professor of Nephrology, Department of Medical Sciences,
Catherine Y. Campbell, M.D. Nephrology Unit, University Hospital, Uppsala, Sweden
Johns Hopkins Hospital, Baltimore, Maryland
Peter Ganz, M.D.
Paul L. Canner, Ph.D. University of California, San Francisco; San Francisco
Maryland Medical Research Institute, Baltimore, Maryland General Hospital, San Francisco, California
Lars A. Carlson, M.D., Ph.D., FRCP Edin Henry N. Ginsberg, M.D.
King Gustaf V Research Institute, Karolinska Institutet, College of Physicians and Surgeons of Columbia University,
Stockholm, Sweden Irving Institute for Clinical and Translational Research,
New York, New York
A. L. Catapano
Professor of Pharmacology, Department of Pharmacological Anne Carol Goldberg, M.D., FACP, FAHA
Sciences, University of Milan, Milan, Italy Washington University School of Medicine, St. Louis, Missouri
ix
FM_i-xx-X5469.indd ix 10/7/08 10:44:12 AM
x Antonio M. Gotto, Jr., M.D., Dphil MacRae F. Linton, M.D.
Weill Cornell Medical College, New York, New York Vanderbilt University Medical Center, Nashville,
Tennessee
John R. Guyton, M.D., FAHA
Duke University Medical Center, Durham, North Carolina Santica M. Marcovina, Ph.D., ScD
Northwest Lipid Metabolism and Diabetes Research

William S. Harris, Ph.D. Laboratories, Department of Medicine, University of
Sanford Research/USD and Sanford School of Medicine, Washington, Seattle, Washington
C
o University of South Dakota, Sioux Falls, South Dakota
n
tr Patrick B. Mark, M.D.
ibu Hallvard Holdaas, M.D., Ph.D. Cardiovascular Research Centre, University of Glasgow,
t
in National Hospital, Oslo, Norway Glasgow, United Kingdom
g
A
ut Ron C. Hoogeveen, Ph.D. Mark E. McGovern, M.D.
h
o Baylor College of Medicine, Houston, Texas Miami Beach, Florida
r
s
Terry A. Jacobson, M.D., FACP, FAHA James M. McKenney, Pharm.D.
Emory University School of Medicine, Atlanta, Georgia National Clinical Research, Richmond, Virginia
Alan G. Jardine, BSc, M.D., FRCP C. Noel Bairey Merz, M.D.
BHF Glasgow Cardiovascular Research Centre, University Cedars-Sinai Medical Center, Women’s Heart Center,
of Glasgow, United Kingdom Los Angeles, California
David J. A. Jenkins, M.D., Ph.D. Michael Miller, M.D., FACC, FANA
Department of Nutritional Sciences, Faculty of Medicine, Division of Cardiology, University of Maryland Hospital,
University of Toronto, Toronto, Ontario, Canada Baltimore, Maryland
Ishwarlal Jialal, M.D., Ph.D. Yury I. Miller, M.D., Ph.D.
University of California Davis Medical Center, Sacramento University of California, San Diego, La Jolla, California
California
Samia Mora, M.D., MHS
Peter H. Jones, M.D. Brigham and Women’s Hospital, Boston, Massachusetts
The Methodist Hospital, Houston, Texas
Patrick M. Moriarty, M.D.
Andrea R. Josse, Bkin, MSc University of Kansas Medical Center, Kansas City, Kansas
Ivor Wynne Centre, Department of Kinesiology, McMaster
University, Ontario, Canada Kiran Musunuru, M.D.
Clinical Fellow, The Johns Hopkins Ciccarone Preventive
Cyril W. C. Kendall, Ph.D. Cardiology Center, Johns Hopkins University School of
Department of Nutritional Sciences, Faculty of Medicine, Medicine, Baltimore, Maryland
University of Toronto, Toronto, Ontario, Canada
Kelly S. Myers, M.D.
Jon A. Kobashigawa, M.D. Mount Sinai School of Medicine, New York, New York
University of California at Los Angeles, Los Angeles, California
Vijay Nambi, MBBS
Marlys L. Koschinsky, B.Sc., Ph.D. Baylor College of Medicine, Houston, Texas,
Queen’s University, Kingston, Ontario, Canada
Tri H. Nguyen, MSc
Penny M. Kris-Etherton, Ph.D., RD University of Toronto, FitzGerald Building, Toronto,
The Pennsylvania State University, Department of Ontario, Canada
Nutritional Sciences, University Park, Pennsylvania
Stephen J. Nicholls, MBBS, Ph.D.
Salila Kurra, M.D. Cleveland Clinic, Cleveland, Ohio
Columbia University College of Physicians and Surgeons,
New York, New York Steven E. Nissen, M.D., MACC
Chairman, Department of Cardiovascular Medicine, Cleveland
Carl J. Lavie, M.D. Clinic Foundation; Professor of Medicine, Cleveland Clinic
Ochsner Health System, New Orleans, Louisiana Lerner School of Medicine at Case
Western Reserve University, Cleveland, Ohio
Ngoc-Anh Le, Ph.D.
Emory University School of Medicine and Atlanta Veterans G. D. Norata, Ph.D.
Affairs Medical Center, Decatur, Georgia Department of Pharmacological Sciences, University of
Milan, Milan, Italy
Peter Libby, M.D.
Mallinckrodt Professor of Medicine, Harvard Medical Melissa Ohlson, MS, RD, LD
School, Chief, Cardiovascular Division, Brigham and Cleveland Clinic, Cleveland, Ohio
Women’s Hospital, Boston, Massachusetts
FM_i-xx-X5469.indd x 10/7/08 10:44:12 AM
Chris J. Packard, DSc, FRCPath, FRCP(Gla), Neil J. Stone M.D., MACP, FAHA, FACC xi
FRSE EurClinChem, CSci, Professor of Clinical Medicine, Feinberg School of
Glasgow Royal Infi rmary, Glasgow, Scotland Medicine, Northwestern University, Chicago, Illinois
F. Xavier Pi-Sunyer, M.D., MPH Allen J. Taylor, M.D., FACC, FAHA
St. Luke’s Roosevelt Hospital Center, Columbia University, Professor of Medicine, Chief, Cardiology Service, Walter

New York, New York Reed Army Medical Center, Washington, D.C.
C
Donna Polk, M.D., MPH Sotirios Tsimikas, M.D., FACC, FAHA, FSCAI o
n
Director of Preventive Cardiology, Hartford Hospital, Professor of Medicine and Director of Vascular Medicine, tr
ib
Hartford, Connecticut University of California, San Diego, La Jolla, California u
t
in
g
Henry J. Pownall, BS, MS, Ph.D. Krishnaswami Vijayaraghavan, M.D., FACP, FACC A
Baylor College of Medicine, Houston, Texas Scottsdale Cardiovascular Center, Scottsdale Clinical ut
h
Research Institute, CV division, Scottsdale Healthcare, o
r
Daniel J. Rader, M.D. Scottsdale, Arizona s
University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania
David Q.-H. Wang, M.D., Ph.D.
Beth Israel Deaconess Medical Center and Harvard Medical
Robert S. Rosenson, M.D.
School, Boston, Massachusetts
Professor of Medicine, Director, Lipoprotein Disorders and
Clinical Atherosclerosis Research Division of Cardiovascu-
Nanette K. Wenger, M.D.
lar Medicine, University of Michigan, Ann Arbor, Michigan
Emory University School of Medicine, Atlanta, Georgia
James H. F. Rudd, M.D., Ph.D., MRCP
Barbara S. Wiggins, Pharm.D., CLS, FAHA
Addenbrooke’s Hospital, Cambridge, United Kingdom
University of Virginia Health System, Charlottesville,
Virginia
Joseph S. Saseen, Pharm.D., FCCP, CLS
University of Colorado Denver, Schools of Pharmacy
and Medicine, Aurora, Colorado Peter W. F. Wilson, M.D.
Emory University School of Medicine, Cardiology and
Gregory G. Schwartz, M.D., Ph.D. Atlanta VAMC Epidemiology and Genetics EPICORE,
Cardiology Section, Denver VA Medical Center and University Atlanta, Georgia
of Colorado Health Sciences Center, Denver, Colorado
Julia M. W. Wong, RD
Udo Seedorf, Ph.D., Dipl.-Biol. Department of Nutritional Sciences, Faculty of Medicine,
Leibniz-Institute of Arteriosclerosis Research, Munster, University of Toronto, Toronto, Ontario, Canada
Germany
Rajagopal V. Sekhar, M.D.
Translational Metabolism Unit, Division of Diabetes,
Endocrinology and Metabolism, Baylor College of
Medicine, Houston, Texas
FM_i-xx-X5469.indd xi 10/7/08 10:44:12 AM
Foreword
Links between lipids and cardiovascular disease made major advances in treating lipid disorders that
emerged over the past century based on laboratory undoubtedly help our patients, much opportunity re-
experiments and observational data in humans. For mains for further inroads and the way forward requires
more than half a century, physicians have used choles- considerable clarifi cation.
terol measurements for assessing the risk of future car- Where can busy practitioners who want the best
diovascular disease. The science of cholesterol has possible outcomes for their patients and need to keep
spawned many Nobel prizes and yielded a daunting abreast of this important, rapidly moving, but challeng-
body of basic science fi ndings. Yet, only in the past two ing fi eld to turn for help? Clinical Lipidology, edited by
decades have practical tools evolved for clinical inter- Dr. Christie Ballantyne as part of the family of compan-
vention on lipids. This recent burgeoning of the evi- ions to Braunwald’s Heart Disease, strives to meet this
dence base supporting clinical benefi t has evolved to need. This text provides an authoritative and compre-
the point where most national guidelines recommend hensive but clinically relevent and practical compen-
therapies that address the lipids profi le. This conver- dium of contemporary lipidology. It spans the scientifi c
gence of new clinical tools and clinical trials have gar- foundations through practical applications to common
nered the attention of practitioners and spurred the clinical scenarios, and does not sidestep the controver-
adoption of lipid treatments by practitioners. sial or unsolved aspects of this fi eld. The authors have
Despite this progress the fi eld of lipidology has en- also, in the individual contributions, casted a glance to
gendered considerable ongoing controversy, confusion, the future to lay the groundwork for rapid uptake of
and frustration. While we have good tools to manipu- anticipated advances.
late low-density lipoprotein (LDL), uncertainty persists The individual chapters by groups of renowned
regarding how, and how far, to lower this cholesterol- experts and noted teachers provide brief but defi nitive
carrying particle. Other prevalent lipid targets such tools and ready reference to guide physicians in their
as high-density lipoprotein (HDL) and lipoprotein (a) daily work. A number of chapters deal succinctly but
[Lp(a)] have proved challenging to modulate in authoritatively with existing and emerging biomarkers
clinically practical ways. A number of approaches relevent to lipidology and cardiovascular risk. The
to modify lipoprotein oxidation and to raise HDL chapters on intervention emphasize those that involve
levels have encountered obstacles during their clinical lifestyle change as well as pharmacologic measures.
development. The chapters provide an evidence-based and scholarly,
The role of advanced lipid testing in daily practice but balanced and accessible, approach to clinical lipi-
remains uncertain. An array of tests confronts the prac- dology. The editors of Braunwald’s Heart Disease
titioner, including lipoprotein particle number, particle expect this unifi ed approach to fi ll an important gap to
size, and apolipoprotein content. How should the enable the practitioner to diagnosis and manage lipid
practicing physician adopt these specialized tests in disorders encountered in daily clinical practice with
the clinic? While many pharmacologic tools exist for confi dence and expertise.
manipulating aspects of the lipid profi le, some prove
challenging to implement in practice due to unwanted Peter Libby, M.D.
actions. Other interventions, although they may pro- Robert O. Bonow, M.D.
duce apparently benefi cial effects on the laboratory Douglas L. Mann, M.D.
fi ndings, have proved elusive in terms of defi ning Douglas P. Zipes, M.D.
clinical benefi t. So, while on the one hand we have Eugene Braunwald, M.D.
xvii
FM_i-xx-X5469.indd xvii 10/7/08 10:44:13 AM
Preface
Cardiovascular disease remains the leading cause of to reduce atherothrombotic cardiovascular events. In
death in industrialized societies, and the majority of addition to understanding the current guidelines and
events are related to atherosclerotic cardiovascular dis- how to implement existing therapies optimally, it is
ease. However, in contrast to cancer, which is the sec- important that physicians understand the evolving tar-
ond leading cause of death, the vast majority of cardio- gets of therapy and in particular the principles and
vascular events could be prevented if individuals were practices required for management of special patient
identifi ed early in life and if preventive measures, in- populations who are high risk for atherosclerotic car-
cluding lifestyle modifi cation and pharmacotherapy, diovascular events.
were initiated. During the last quarter of a century, ex- This textbook has been developed to be useful for
traordinary developments in the fi eld of preventive cardiologists, endocrinologists, internists, family prac-
cardiology, with tremendous advances in basic science titioners, physician assistants, nurses, pharmacists, and
and clinical research in the area of lipids, lipoproteins, other healthcare professionals who want in-depth, state-
and atherosclerosis, have led to continual improve- of-the-art information on the treatment of lipids and
ments in clinical practice. This textbook has been writ- atherosclerosis. We hope that it will serve as an impor-
ten for both practicing clinicians and students who are tant resource for students and trainees. I was personally
interested in effective management of lipids for the motivated to go into the fi eld of cardiovascular disease
treatment and prevention of cardiovascular disease. because my father had a myocardial infarction compli-
The textbook has been divided into three major sec- cated by ventricular fi brillation when I was in high
tions: mechanisms, risk assessment, and therapy. Opti- school, my father’s sister died of a myocardial infarc-
mal clinical care requires understanding the basic tion when I was in medical school, and I helped take
mechanisms involving lipoprotein metabolism, genet- care of my mother’s brother after he suffered a large
ics, and atherosclerosis, which are covered in the fi rst stroke complicated by expressive aphasia and hemipa-
section. This fundamental knowledge can be translated resis while I was training as a cardiology fellow. We
into clinical benefi ts for patients by using a systematic clearly now have both the knowledge and the therapies
two-step process of screening followed by targeted in- to prevent the vast majority of heart attacks and strokes
terventions. The fi rst step involves global risk assess- that occur in our patients, and it is my greatest hope
ment to identify individuals who have increased risk that the information in this book will be used in the
for developing atherosclerotic cardiovascular events, successful implementation of strategies to manage lip-
and the second step is to implement therapeutic inter- ids and other risk factors to prevent pain, suffering, and
ventions targeted to correct metabolic derangements, death from atherosclerotic cardiovascular disease.
using both lifestyle modifi cations and pharmacotherapy Christie M. Ballantyne, M.D.
xix
FM_i-xx-X5469.indd xix 10/7/08 10:44:13 AM
I
SECTION
Basic Mechanisms
1
C H A P T E R
The Lipoproteins, 1 Human Plasma Lipoprotein Metabolism
Lipoprotein Properties, 1
Lipoprotein Production, 3 Henry J. Pownall and Antonio M. Gotto, Jr.
THE LIPOPROTEINS
and provided new targets for pharma-
cologic management of dyslipidemia
Introduction
and atherosclerosis.
The French physician-scientist Michel
Macheboeuf is acknowledged as the
father of plasma lipoproteins. His LIPOPROTEIN PROPERTIES
seminal 1928 discovery fi ts the adage
that science usually precedes tech- The plasma lipoproteins are composed
nology, in this case by several de- of neutral lipids, polar lipids, and spe-
cades. In his doctoral thesis, Recher- cialized proteins called apolipopro-
ches sur les lipides, les stérols et les teins (apos). The major neutral lipids
protéides du sérum et du plasma san- are cholesteryl esters (CEs) and triglyc-
guinis, Macheboeuf described horse erides (TGs); the polar lipids are phos-
serum lipoproteins, demonstrating phatidylcholine, sphingomyelin, and
the association of lipids and proteins, free cholesterol with small amounts of
ìlipido-protéidiquesî, in plasma.1 It is phosphatidylethanolamine and traces
now recognized that plasma lipids of other phospholipids (PLs). The com-
are transported by lipoproteins, which positions of the lipoproteins determine
are defi ned by the densities at which their size and structures (Table 1-1).
they are isolated, that is, as the Lipoprotein size and density are a di-
high-, low-, intermediate-, and very- rect function of neutral lipid content,
low-density lipoproteins (HDLs, LDLs, with the largest lipoprotein particles
IDLs, and VLDLs, respectively); chy- being the least dense and having the
lomicrons, which are intestinally de- highest ratio of neutral to polar lipids.
rived, are composed mainly of dietary Surface charge as revealed by agarose
lipids and small amounts of protein. gel electrophoresis varies among lipo-
HDL appears in two subclasses, HDL proteins according to the amount of
2
and HDL . Through a simple veni- charged lipids and the conformations
3
puncture, plasma lipoprotein levels, of their apos. Lipoproteins have been
which are arguably among the most isolated according to size, charge, and
important risk factors for coronary density by size exclusion chromatogra-
artery disease, provide clues about phy, ion exchange chromatography,
the etiology of lipid disorders and and ultracentrifugation, respectively,
about their most prominent patho- with the latter technique being used for
logic sequela, atherosclerosis. From preparative isolation.
this window on life, a host of infor- The organization of the remainder of
mative analyses has emerged. Corr- this chapter proceeds from our view that
elations between coronary artery much of the currently unanswered lipid
disease and the properties, composi- and lipoprotein pathologies proceed from
tions, and plasma concentrations of dysregulated fatty acid metabolism,
various analytes—lipids as well as which is important in numerous diseases
lipoproteins—have revealed mecha- of public interest, including obesity,
nisms that ultimately aided diagnosis diabetes, and atherosclerosis. Although
Ch01_001-010-X5469.indd 1 10/6/08 1:13:50 PM
2
TABLE 1-1 Properties of Human Plasma Lipoproteins
Composition (%)
Core Surface
Class D (nm) d (g/mL) Mobility TG CE FC PL Pro Major Apos
CH 1
Chylomicrons 80–500 (cid:2)0.93 α2 86 3 2 7 2 B-48, E, A-I, A-II, A-IV, C
VLDL 30–80 0.95–1.006 Pre-β 55 12 7 18 8 B-100, C-I, C-II, C-III, E
IDL 25–35 1.006–1.019 Slow pre-β 23 29 9 19 19 B-100, E
LDL 21.6 1.019–1.063 β 6 42 8 22 22 B-100
HDL 10 1.063–1.125 α 5 17 5 33 40 A-I, A-II
2
HDL 7.5 1.125–1.210 α 3 13 4 25 55 A-I, A-II
3
Lp(a) 30 1.055–1.085 Slow pre-β 3 33 9 22 33 B-100, apo(a)
apos, apolipoproteins; D, diameter; d, density; CE, cholesteryl ester; FC, free cholesterol; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein(s); LDL, low-density
lipoprotein; Lp(a), lipoprotein(a); PL, phospholipid; TG, triglyceride(s); VLDL, very-low-density lipoprotein(s).
many of the downstream effects of dysregulated fatty acid esterify glycerol-3-phosphate via the Kennedy pathway
metabolism are the targets of therapy, it remains important for glycerolipid synthesis. The TGs so formed associate
to identify therapeutic modalities that might address un- in TG droplets that are visible under light microscopy
derlying causes. (Fig. 1-1). The surfaces of the droplets are surrounded by
a mixed monomolecular layer of PLs and by specialized
proteins that are essential to normal TG storage and
hydrolysis, including perilipin, Comparative Gene
Nonesterifi ed Fatty Acids
Identifi cation–58 (CGI–58), and microsomal transfer pro
Some plasma nonesterifi ed fatty acids (NEFAs) are de- tein (MTP)-B, a splicing variant of the canonical MTP-A
rived from VLDL- and chylomicron-TG hydrolysis by li- that is found in liver and is associated with protein disul-
poprotein lipase (LPL), which is attached to the capillary fi de isomerase. Whereas MTB-B mediates fusion of small
endothelium via proteoglycans. A small fraction of the fat droplets into larger ones,2 it has no direct effect on
released NEFAs is released into the plasma, particularly lipolysis. In contrast, perilipin and CGI–58 are important
in the postprandial state, when rates of chylomicron-TG in the regulation of adipocyte lipolysis, and under fasting
hydrolysis are high. Most of the liberated NEFAs trans- conditions, AT TG is a major source of plasma NEFAs.
migrate the endothelium to adipose tissue (AT), where In the absence of stimulation, perilipin on the sur-
they diffuse across the adipocyte plasma membrane and face of fat droplets blocks hormone-sensitive lipase
A 10 μm B 10 μm
FIGURE 1-1 Confocal microscopy of MTP
in 3T3-L1 cells. A, Fixed 3T3 cells were
probed with anti-microsomal triglyceride
transfer protein (MTP) followed by a second
Cy3-conjugated antibody. Fluorescence
occurred throughout the cell but was more
profound in juxtanuclear regions. (B–E)
Differentiated 3T3 cellsDocument1. MTP
fl uorescence was higher throughout com-
pared with nondifferentiated cells and was
observed around lipid droplets (E), espe-
cially the smaller droplets. Signals in the
C 10 μm D 10 μm E 4 μm juxtanuclear regions remained prominent
(C, D). (From Ref. 2, with permission.)
Ch01_001-010-X5469.indd 2 10/6/08 1:13:51 PM