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Bryan Brewer, who was born in Casper, Wyoming, on 17 August 1938, is presently the
Director, Lipoprotein and Atherosclerosis Research, Cardiovascular Research Institute,
MedStar Research Institute, Washington Hospital Center in Washington, DC. After attending
public schools in Casper, Dr. Brewer graduated from The Johns Hopkins University in
Baltimore with a BA degree in biological chemistry in 1960 and from the Stanford University
School of Medicine in Stanford, California, in 1965. His internship and residency
in internal medicine were at the Massachusetts General Hospital in Boston. After 2
years of training, he went to the National Institutes of Health as a clinical associate
in what was then the National Heart Institute (later, National Heart, Lung, and Blood
Institute) at the National Institutes of Health in Bethesda, Maryland. By 1970, he
was head of the section on peptide chemistry of the Molecular Disease Branch in the
National Heart Institute, and in 1976 he was appointed Chief of the Molecular Disease
Branch. He remained in that position until 2005, when he assumed his present position.
During his nearly 36 years at the NIH, Dr. Brewer ran an extremely productive laboratory.
His investigations led to publication of 470 articles in peer-review medical journals.
His research work has included the elucidation of cholesterol and lipoprotein metabolism
in normal subjects and in patients with genetic dyslipoproteinemias; the use of transgenic
and knock-out animal models to determine the role of specific genes modulating lipoprotein
metabolism and atherosclerosis; and diagnosis and treatment of patients with disorders
of cholesterol and triglycerides with the ultimate goal of developing gene specific
diagnoses as well as treatment of patients at risk for the development of cardiovascular
disease. For his work, he has received several honors, and he has been a featured
speaker at numerous medical meetings. Bryan Brewer is also a good guy and fun to be
around (Figure 1).
Figure 1Recent photograph of Hollis Bryan Brewer, Jr., MD.
Proc Natl Acad Sci USA.1974; 71 (Dr. Brewer’s comment: Molecular model of HDL apolipoprotein-lipid interaction illustrating that the characteristic feature of the apolipoprotein was an amphipathic helix with 1 surface hydrophobic and 1 surface hydrophilic): 1534-1538
The self-association of the reduced apoA-II apoprotein from the human high density lipoprotein complex.
Biochem.1975; 14 (Dr. Brewer’s comment: Demonstration that human apolipoproteins self associate into discrete oligomeric complexes with marked increases in secondary and tertiary structure with association): 3741-3746
Advances in Protein Chemistry. Vol. 31. Academic Press,
New York1977 (Dr. Brewer’s comment: Detailed review that summarized the discovery that the human plasma apolipoproteins, in contrast to classical proteins, could change from a random coil to a globular protein when interacting with lipids or during self association)
The amino acid sequence of human apoA-I, an apolipoprotein isolated from high density lipoproteins.
Biochem Biophys Res Commun.1978; 80 (Dr. Brewer’s comment: Amino acid sequence of the major HDL apolipoprotein, apoA-I which is the major ligand for cholesterol efflux from cells): 623-630
Metabolism of high density lipoproteins in Tangier Disease.
N Engl J Med.1978; 299 (Dr. Brewer’s comment: First demonstration that the low plasma HDL in Tangier disease was due to increased HDL catabolism and changed the prevailing concept that the low HDL was due to decreased HDL production): 905-910
Coronary heart disease prevalence and other clinical features in familial high density lipoprotein deficiency (Tangier disease).
Ann Int Med.1980; 93 (Dr. Brewer’s comment: Initial report of a review of the cases of Tangier disease establishing that low HDL in Tangier disease was associated with an increased risk of cardiovascular disease): 261-266
The metabolism of high density lipoprotein subfractions and constituents in Tangier disease following the infusion of high density lipoproteins.
J Lipid Res.1981; 22 (Dr. Brewer’s comment: Metabolic study in a Tangier disease patient following an infusion of normal HDL to increase the plasma HDL to control levels. HDL catabolism was increased despite the normal plasma level of HDL, establishing that the increased catabolism of radiolabeled HDL observed in the kinetic studies in Tangier disease patients was not due to a decreased HDL pool size): 217-228
Sci.1981; 211 (Dr. Brewer’s comment: Clinical study which established that the genetic defect in type III hyperlipoproteinemia [dysbetalipoproteineima] was due to a structural defect and loss of function of apolipoprotein E): 584-586
Type III hyperlipoproteinemia associated with apolipoprotein E deficiency.
Science.1981; 214 (Dr. Brewer’s comment: Initial identification of a kindred with a mutation in apo-E resulting in apo-E deficiency and type III hyperlipoproteinemia): 1239-1241
J Lipid Res.1982; 23 (Dr. Brewer’s comment: Analysis of HDL metabolism in humans using radiolabeled apolipoproteins A-I and A-II. A new approach to lipoprotein kinetics using radiolabeled apolipoproteins reassociated with plasma lipoproteins): 850-862
J Lipid Res.1983; 24 (Dr. Brewer’s comment: Compartmental model of HDL metabolism in humans based on apolipoprotein kinetics in control subjects. Model served as a basis for analysis of HDL kinetic studies in patients with genetic defects in lipoprotein metabolism): 60-71
Biochem Biophys Res Commun.1983; 112 (Dr. Brewer’s comment: Nucleotide sequence of preproapoA-I. Identification that apo-A-I was synthesized as a preproapolipoprotein): 257-264
Ann Int Med.1983; 98 (Dr. Brewer’s comment: Review of the data on the clinical, biochemical, and genetic defect in patients with type III hyperlipoproteinemia): 623-640
J Clin Endocrinol Metab.1983; 57 (Dr. Brewer’s comment: Characterization of the apo-E2 isoform of apoE associated with type III hyperlipoproteinemia): 969-974
Amino acid sequence of human apolipoprotein C-II from normal and hyperlipoproteinemic subjects.
J Biol Chem.1984; 259 (Dr. Brewer’s comment: Amino acid sequence of human apoC-II, the apolipoprotein which is the co-factor for lipoprotein lipase): 318-322
Analysis of the apoC-II gene in apoC-II deficient patients.
Biochem Biophys Res Commun.1983; 124 (Dr. Brewer’s comment: Initial report of a structural defect in apo-C-II resuling in hypertriglyceridemia and type I hyperlipoproteinemia [familial hyperchylomicronemia syndrome].): 308-313
Proc Natl Acad Sci USA.1984; 81 (Dr. Brewer’s comment: Complete genomic sequence of preapoC-II. Sequence used in the characterization of patients with apo-C-II deficiency and type I hyperlipoproteinemia [familial hyperchylomicronemia syndrome]).): 6354-6357
Two-dimensional electrophoresis of human plasma apolipoproteins.
Clin Chem.1984; 30 (Dr. Brewer’s comment: Initial report utilizing 2-dimensional gel electrophoresis in the characterization of the human plasma apolipoproteins): 2084-2092
Metabolism.1985; 34 (Dr. Brewer’s comment: Analysis of the tissue distribution in humans of the synthesis of the apoB-100 and apoB-48 isoforms): 726-730
J Lipid Res.1985; 26 (Dr. Brewer’s comment: Kinetic study in man establishing that apo-A-I was synthesized and secreted as a proprotein and converted in plasma by a protease to mature apo-A-I): 185-193
J Biol Chem.1985; 260 (Dr. Brewer’s comment: Analysis of the nucleotide sequence of apo-A-I, establishing that the molecular defect in Tangier disease was not due to a structural mutation in apo-A-I): 12810-12814
Proc Natl Acad Sci USA.1986; 83 (Dr. Brewer’s comment: Elucidation of the amino acid sequence of human apoB-100, the major structural apolipoprotein of LDL): 8142-8146
Identification of a novel in-frame translational stop codon in human intestine apoB mRNA.
Biochem Biophys Res Commun.1987; 148 (Dr. Brewer’s comment: Identification of the stop codon in the apo-B mRNA identifying the novel molecular RNA editing mechanism responsible for the synthesis of 2 apolipoproteins, apoB-100 and apoB-48, from a single gene): 279-285
Expression of apolipoprotein B mRNAs encoding higher- and lower-molecular weight isoproteins in rat liver and intestine.
Proc Natl Acad Sci USA.1989; 86 (Dr. Brewer’s comment: Study that established that RNA editing in the rat liver resulted in the synthesis of both apo-B-100 and apo-B-48, which was in contrast to the human liver which synthesized only apo-B-100. The rapid catabolism of plasma apo-B in the rat was due to the increased synthesis of the rapidly catabolized apoB-48 isoform of apo-B): 500-504
Proc Natl Acad Sci USA.1990; 87 (Dr. Brewer’s comment: Intial report of a molecular defect in lipoprotein lipase resulting in hypertriglyceridemia and type I hyperlipoproteinemia [Familial Hyperchylomicronemia Syndrome]).): 3474-3478
In vivo protein metabolism utilizing stable isotopes and mass spectrometry.
in: Association of American Physicians. CIII. 1990: 187-194 (Dr. Brewer’s comment: Description of the development of the stable isotope technique to study lipoprotein metabolism in humans)
A mutation in apolipoprotein A-I in the Iowa type of familial amyloidotic polyneuropathy.
Genomics.1990; 8 (Dr. Brewer’s comment: Discovery that a structural mutation in apo-A-I was the genetic defect in a kindred with family amyloidosis establishing that structural changes in the A-I apolipoprotein could result in the cellular accumulation of the abnormal protein leading to amyloidosis): 318-323
JAMA.1991; 265 (Dr. Brewer’s comment: Review of molecular defects in lipoprotein lipase resulting in hypertriglyceridemia and type I hyperlipidemia): 904-908
In vivo metabolism of apolipoprotein A-I on high density lipoprotein particles LpA-I and LpA-I, A-II.
J Lipid Res.1991; 32 (Dr. Brewer’s comment: Analysis of the metabolism of the 2 major lipoprotein particles in HDL, LpA-I and LpA-I,A-II in humans): 1849-1859
Human lipoprotein lipase. Analysis of the catalytic triad by site-directed mutagenesis of Ser-132, Asp-156, and His-241.
J Biol Chem.1992; 267 (Dr. Brewer’s comment: Identification of the amino acid residues in the catalytic site modulating lipoprotein lipase activity): 4161-4165
Two different allelic mutations in the lecithin-cholesterol acyltransferase gene associated with the fish eye syndrome. Lecithin-cholesterol acyltransferase (Thr123→Ile) and lecithin-cholesterol acyltransferase (Thr347→Met).
J Clin Invest.1992; 89 (Dr. Brewer’s comment: Identification of the molecular defects in the LCAT gene resulting in Fish eye disease): 499-506
J Biol Chem.1992; 267 (Dr. Brewer’s comment: Analysis provided evidence that lipoprotein lipase contains a loop of amino acids that covers the active site of the enzyme and is a primary site of interaction with lipids): 25086-25091
In vivo metabolism of a mutant apolipoprotein, apoA-IIowa, associated with hypoalphalipoproteinemia and hereditary systemic amyloidosis.
J Lipid Res.1992; 33 (Dr. Brewer’s comment: Metabolic study that established that the mutant A-I apolipoprotein, apo-A-IIowa, which accumulates in this form of amyloidosis, was rapidly catabolized, resulting in low plasma HDL levels): 755-763
J Clin Invest.1993; 92 (Dr. Brewer’s comment: Clinical and biochemical analysis that established that the different clinical features of classical LCAT deficicany and Fish eye disease were due to differences in residual LCAT acitivity in the individual patient rather than a defect in 2 separate genes coding for the LCAT enzyme): 479-485
In vivo metabolism of a mutant form of apolipoprotein A-I, apo A-IMilano associated with familial hypoalphalipoproteinemia.
J Clin Invest.1993; 91 (Dr. Brewer’s comment: Pivotal metabolic study in Italian patients providing evidence that the low plasma HDL levels in apo-A-I Milano were due to increased catabolism of the mutant A-I apolipoprotein): 1445-1452
Increased production of apolipoprotein A-I associated with elevated plasma levels of high-density lipoproteins, apolipoprotein A-I, and lipoprotein A-I in a patient with familial hyperalphalipoproteinemia.
Metab.1993; 42 (Dr. Brewer’s comment: First reported kindred with high plasma HDL levels due to increased synthesis of apo-A-I): 1429-1434
Delayed catabolism of high density lipoprotein apolipoprotein A-I and A-II in human cholesteryl ester transfer protein deficiency.
J Clin Invest.1993; 92 (Dr. Brewer’s comment: HDL kinetic study in Japanese patients with CETP deficiency, establishing that the increase plasma HDL levels were due to decreased HDL catabolism): 1650-1658
Markedly acclerated catabolism of apolipoprotein A-II (apoA-II) and high density lipoproteins containing apoA-II in classic lecithin.
J Clin Invest.1994; 93 (Dr. Brewer’s comment: HDL metabolic study that indicated that the low plasma HDL levels in LCAT deficiency and Fish eye disease were due to rapid catabolism of a poorly lipidated HDL): 321-330
Characterization of high-density apolipoprotein particles A-I and A-I.
Eur J Biochem.1995; 227 (Dr. Brewer’s comment: Detailed characterization of the very large HDL particles that are present in patients with CETP deficiency): 123-129
Overexpression of human lecithin cholesterol acyltransferase leads to hyperalphalipoproteinemia in transgenic mice.
J Biol Chem.1995; 270 (Dr. Brewer’s comment: Overexpression of LCAT leads to marked increases in plasma HDL in mice that lack CETP, indicating that modulation of LCAT activity can significantly effect plasma HDL levels): 12269-12275
Apolipoprotein E deficiency in mice: gene replacement and prevention of atherosclerosis using adenovirus vectors.
J Clin Invest.1995; 96 (Dr. Brewer’s comment: First report of the correction of a genetic defect in lipoprotein metabolism using adenovirus delivery of the normal gene): 1612-1620
Increased catabolic rate of low density lipoproteins in humans with cholesteryl ester transfer protein deficiency.
J Clin Invest.1995; 96 (Dr. Brewer’s comment: Kinetic study in Japanese patients with CETP deficiency that revealed that the composition and metabolism of LDL was abnormal and the explanation for the low LDL levels in CETP deficiency was increased catabolism of abnormal LDL): 1573-1581
Hepatic lipase gene therapy in hepatic lipase deficient mice.
J Clin Invest.1996; 97 (Dr. Brewer’s comment: First evidence that a deficiency of an endothelial bound plasma lipolytic enzyme, hepatic lipase, in a hepatic lipase deficient animal model could be replaced by the delivery of the normal gene using adenovirus vectors directed to the liver): 799-805
Lecithin-cholesterol acyltransferase overexpression generates hyperalphalipoproteinemia and nonatherogenic lipoprotein pattern in transgenic rabbits.
J Biol Chem.1996; 271 (Dr. Brewer’s comment: First report of the development of transgenic rabbits for the analysis of genes that modulate lipoprotein metabolism): 4396-4402
Hyperalphalipoproteinemia in human LCAT transgenic rabbits.
J Clin Invest.1996; 97 (Dr. Brewer’s comment: Metabolic study indicating that the marked increase in plasma HDL levels with overexpression of the LCAT gene was due to decreased catabolism of apo-A-I): 1844-1851
Overexpression of lecithin:cholesterol acyltransferase in transgenic rabbits prevents diet-induced atherosclerosis.
Proc Natl Acad Sci USA.1996; 3 (Dr. Brewer’s comment: Pivotal study that established that overexpression of LCAT resulted in increased HDL levels and decreased atherosclerosis. These results indicated that modulation of LCAT activity is an attractive target for the development of new agents to treat atherosclerosis in man): 11448-11453
J Biol Chem.1997; 272 (Dr. Brewer’s comment: Development of a LCAT knockout mouse model to study the effects of the LCAT gene on lipoprotein metabolism and atherosclerosis): 7506-7510
J Biol Chem.1997; 43 (Dr. Brewer’s comment: Results indicated that overexpression of phospholipid transfer protein decreased HDL levels, increased cellular uptake of lipids, and induced heterogeneity of the size of HDL ranging from smaller to larger HDL particles): 27393-27400
Decreased reverse cholesterol transport from Tangier disease fibroblasts. Acceptor specificity and effect of brefeldin on lipid efflux.
Arterioscler Thromb Vasc Biol.1997; 17 (Dr. Brewer’s comment: In vitro cell culture study showing that cholesterol efflux from Tangier disease fibroblasts was decreased, which is consistent with the concept that the molecular defect in Tangier disease was a cellular defect in cholesterol efflux): 1813-1821
Cubilin, the endocytic receptor for intrinsic factor-vitamin b12 complex, mediates high density lipoprotein holoparticle endocytosis.
Proc Natl Acad Sci USA. 1999 (Dr. Brewer’s comment: Studies suggest that the cubilin system present in the kidney may play an important role in the metabolism of HDL)
Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.
Nat Genet.1999; 22 (Dr. Brewer’s comment: Analysis revealed the genetic defect in Tangier disease was a defect in the ABCA1 transporter that regulates cellular cholesterol efflux): 352-355
Proc Natl Acad Sci USA.1999; 97 (Dr. Brewer’s comment: Identification of the molecular defect in the first kindred with Tangier diease that presented to the NIH with low HDL levels in the 1960s. In addition, the complete genomic sequence of the ABCA1transporter was reported): 12685-12690
Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice.
J Biol Chem.2000; 274 (Dr. Brewer’s comment: LCAT transgenic mice were shown to have increased atherosclerosis due to a large dysfunctional HDL. Expression of CETP in this model reduced the abnormal HDL and decreased atheroscslerosis. Results from this study indicated that increased HDL may not always protect against atherosclerosis, and an analysis of the function as well as the level of HDL is necessary to determine the potential protection of HDL in the development of atherosclerosis): 36912-36920
In vivo evidence for both lipolytic and nonlipolytic function of hepatic lipase in the metabolism of HDL.
Arterioscler Thromb Vasc Biol.2000; 20 (Dr. Brewer’s comment: In vivo studies that showed that hepatic lipase could function both as a lipolytic enzyme as well as a ligand for the cellular uptake of lipids and lipoproteins): 793-800
Curr Opin Lipidol.2000; 11 (Dr. Brewer’s comment: A review that summarized the new concept that plasma enzymes can function both as enzymes modulating lipoprotein metabolism as well as ligands for the cellular uptake of lipids and lipoprotein particles): 267-275
Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterol acyltransferase-deficient mice.
J Biol Chem.2001; 4 (Dr. Brewer’s comment: LCAT transgenic mouse model used to demonstrate the absence of LCAT activity was responsible for the renal defect in LCAT deficiency) (15090–98): 276
Cellular localization and trafficking of the human ABCA1 transporter.
J Biol Chem.2001; 276 (Dr. Brewer’s comment: Analysis of the cellular trafficking of the ABCA1 transporter revealed that the transporter was present not only on the cell surface but also trafficked to the late endocytic compartment within the cell): 27584-27590
Regulation and intracellular trafficking of the ABCA1 transporter.
J Lipid Res.2001; 42 (Dr. Brewer’s comment: A review that summarized the data to support the concept that the ABCA1 transport had a surface as well as intracellular pathway involved in the efflux of cellular cholesterol): 1339-1345
Apolipoprotein specificity for lipid efflux by the human ABCAI transporter.
Biochem Biophys Res Commun.2001; 280 (Dr. Brewer’s comment: Pivotal result that estabolished that several of the apolipoproteins, including apoA-II and apoE in addition to apoA-I, were able to bind to the ABCA1 transporter and facilitate cholesterol efflux): 818-823
A normal rate of cellular cholesterol removal can be mediated by plasma from a patient with familial lecithin-cholesterol acyltransferase (LCAT) deficiency.
Clin Chim Acta.2001; 314 (Dr. Brewer’s comment: LCAT deficient plasma was able to stimulate cellular cholesterol efflux, providing a reason for the lack of increased atherosclerois in LCAT deficient patients. The lipidated nacent HDL is unable to form a mature HDL due to the deficiency of LCAT, which esterifies free cholesterol to cholesterlyl esters. The partially lipidated nascent HDL particles are filtered by the kidney and catabolized, resulting in the low plasma HDL levels in LCAT deficient patients): 131-139
The ATP binding cassette transporter A1 (ABCA1) modulates the development of aortic atherosclerosis in C57Bl/6 and apoE-knockout mice.
PNAS.2002; 99 (Dr. Brewer’s comment: Atherosclerosis in ABCA1 transgenic mice was increased and associated with increased plasma LDL levels suggesting that overexpression of the hepatic ABACA1 transporter was associated with increased HDL as well as LDL in these experimental mouse model systems): 407-412
The ABCA1 transporter functions on the basolateral surface of hepatocytes.
Biochem Biophys Res Comm.2002; 297 (Dr. Brewer’s comment: The ABCA1 transporter was shown to be localized to the basolateral side in the liver. Increased expression of hepatic ABCA1 would result in increased HDL in the plasma rather than increased delivery of cholesterol to the bile): 974-979
In vivo metabolism of apolipoprotein E within the HDL subpopulations LpE, LpE:A-I, LpE:A-II and LpE:A-I:A-II.
Atherosclerosis.2002; 165 (Dr. Brewer’s comment: The subpopulation of HDL containing apoE had markedly increased catabolism when compared to the apoE–free LpA-I and LpA-I,A-II particles): 205-220
Role of the hepatic ABCA1 transporter in modulating intrahepatic cholesterol and plasma HDL-cholesterol concentrations.
J Lipid Res.2003; 44 (Dr. Brewer’s comment: Pivotal study that demonstrated that increased expression of the hepatic ABCA1 transporter resulted in increased HDL and, in addition, LDL levels due to transfer of HDL cholesterol to LDL. These studies suggest that increased ABCA1 expression in the liver may not result in protection against the development of atherosclerosis due to the increased LDL cholesterol levels): 296-302
Synthetic amphipathic helical peptides promote lipid efflux from cells by an ABCA1-dependent and an ABCA1-independent pathway.
J Lipid Res.2003; 44 (Dr. Brewer’s comment: Detailed analysis of structure–function requires for the binding and efflux of cholesterol from the ABCA1 transporter) (2003): 828-836
The ABCA1 transporter modulates late endocytic trafficking.
J Biol Chem.2004; 279 (Dr. Brewer’s comment: Correction of the genetic defect in Tangier disease resulted in a decrease in the intracellular pool of cholesterol in the late endocytic compartment characteristic of Tangier disease and restoration of cellular cholesterol efflux. These results substantiated the important role and intracellular trafficking of the ABCA1transporter in cellular cholesterol metabolism): 15571-15578
Arterioscler Thromb Vasc Biol.2004; 24 (Dr. Brewer’s comment: Review of HDL function, metabolism, and developing role as an important therapeutic target for the treatment of the high-risk patient with cardiovascular disease): 387-391
N Engl J Med.2004; 350 (Dr. Brewer’s comment: Conceptual view of the potential role of HDL in the treatment of patients at risk for cardiovascular disease. HDL therapy can be divided into acute therapy to reduce vulnerable plaques by IV infusion in patients with the acute coronary syndrome and oral chronic HDL therapy to reduced the risk of cardiovascular disease): 1491-1494
Serum amyloid A promotes ABCA1-dependent and ABCA1-independent lipid efflux from cells.
Biochem Biophys Res Comm.2004; 321 (Dr. Brewer’s comment: Serum amyloid A is increased on plasma HDL during acute imflammation. Serum amyloid like apo-A-I and other plasma apolipoproteins was shown to facilitate cellular efflux): 936-941
AHA Scientific Sessions 2002 George Lyman Duff Memorial Lecture. Regulation of HDL metabolism by the ABCA1 transporter and the emerging role of HDL in the treatment of cardiovascular disease.
Arterioscler Thromb Vasc Biol.2004; 24 (Dr. Brewer’s comment: Invited lecture that summarizes the role of the ABCA1 transporter in cholesterol efflux and the potential use of HDL to treat patients at risk for cardiovascular disease): 1755-1760
