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HOLLIS BRYAN BREWER, JR., MD: A Conversation With the Editor

        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 thumbnail gr1
        Figure 1Recent photograph of Hollis Bryan Brewer, Jr., MD.
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        Best Publications as selected by Hollis Bryan Brewer, Jr., MD

          • Brewer Jr., H.B.
          • Shulman R.
          • Herbert P.
          • Ronan R.
          • Wehrly K.
          The complete amino acid sequence of an apolipoprotein obtained from human very low density lipoprotein (VLDL).
          Adv Exp Med Biol. 1972; 25 (Dr. Brewer’s comment: First report of a sequence of a human plasma apolipoprotein, apo-C-III): 280-281
          • Brewer Jr., H.B.
          • Lux S.E.
          • Ronan R.
          • John K.M.
          The complete amino acid sequence of a human plasma high density apolipoprotein, apoLp-gln-II (A-II).
          Proc Natl Acad Sci USA. 1972; 69 (Dr. Brewer’s comment: First amino acid sequence of a HDL apolipoprotein, apoA-II.)): 1304-1308
          • Assmann G.
          • Brewer Jr., H.B.
          A molecular model of high density lipoproteins.
          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
          • Osborne J.C.
          • Palumbo G.
          • Brewer Jr., H.B.
          • Edelhoch H.
          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
          • Osborne Jr., J.C.
          • Brewer Jr., H.B.
          The plasma lipoproteins.
          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)
          • Brewer Jr., H.B.
          • Fairwell T.
          • LaRue A.
          • Ronan R.
          • Houser A.
          • Bronzert T.J.
          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
          • Schaefer E.J.
          • Blum C.R.
          • Levy R.I.
          • Jenkins L.L.
          • Alaupovic P.
          • Foster D.M.
          • Brewer Jr., H.B.
          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
          • Schaefer E.J.
          • Zech L.A.
          • Schwartz D.S.
          • Brewer Jr., H.B.
          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
          • Schaefer E.J.
          • Anderson D.W.
          • Zech L.A.
          • Lindgren F.T.
          • Bronzert T.J.
          • Rubalcaba E.A.
          • Brewer Jr., H.B.
          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
          • Gregg R.E.
          • Zech L.A.
          • Schaefer E.J.
          • Brewer Jr., H.B.
          Type III hyperlipoproteinemia.
          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
          • Ghiselli G.
          • Shaefer E.J.
          • Gascon P.
          • Brewer Jr., H.B.
          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
          • Schaefer E.J.
          • Zech L.A.
          • Jenkins L.L.
          • Aamodt R.A.
          • Bronzert T.J.
          • Rubalcaba E.A.
          • Lindgren F.T.
          • Brewer Jr., H.B.
          Human apolipoprotein A-I and A-II metabolism.
          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
          • Zech L.A.S.
          • Schaefer E.J.
          • Bronzert T.J.
          • Aamodt R.L.
          • Brewer Jr., H.B.
          Metabolism of human apolipoproteins A-I and A-II.
          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
          • Law S.W.
          • Gray G.
          • Brewer Jr., H.B.
          cDNA cloning of human apoA-I.
          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
          • Brewer Jr., H.B.
          • Zech L.A.
          • Gregg R.E.
          • Schwartz D.
          • Schaefer E.J.
          Type III hyperlipoproteinemia.
          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
          • Gregg R.E.
          • Ghiselli G.
          • Brewer Jr., H.B.
          Apolipoprotein E.
          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
          • Hospattankar A.
          • Fairwell T.
          • Ronan R.
          • Brewer Jr., H.B.
          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
          • Fojo S.S.
          • Law S.W.
          • Sprecher D.L.
          • Gregg R.E.
          • Baggio G.
          • Brewer Jr., H.B.
          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
          • Fojo S.S.
          • Law S.W.
          • Brewer Jr., H.B.
          Human apolipoprotein C-II.
          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
          • Sprecher D.L.
          • Taam L.
          • Brewer Jr., H.B.
          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
          • Gregg R.E.
          • Zech L.A.
          • Schaefer E.J.
          • Brewer Jr., H.B.
          Apolipoprotein E metabolism in normal lipoproteinemic human subjects.
          J Lipid Res. 1984; 25 (Dr. Brewer’s comment: Detailed review of the metabolism of apo-E in humans): 1167-1176
          • Lackner K.J.
          • Law S.W.
          • Brewer Jr., H.B.
          The human apolipoprotein A-II gene.
          Nucleic Acids Res. 1985; 13 (Dr. Brewer’s comment: Characterization of the gene of preproapoA-II, a major HDL apolipoprotein): 4597-4608
          • Edge S.B.
          • Hoeg J.M.
          • Schneider P.D.
          • Brewer Jr., H.B.
          Apolipoprotein B synthesis in humans.
          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
          • Bojanovski D.
          • Gregg R.E.
          • Ghiselli G.
          • Schaefer E.J.
          • Light J.A.
          • Brewer Jr., H.B.
          Human apolipoprotein A-I isoprotein metabolism.
          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
          • Law S.W.
          • Brewer Jr., H.B.
          Tangier disease.
          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
          • Law S.W.
          • Grant S.M.
          • Higuchi K.
          • Hospattankar A.
          • Lackner K.
          • Lee N.
          • Brewer Jr., H.B.
          Human liver apolipoprotein B-100 cDNA.
          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
          • Schaefer E.J.
          • Gregg R.E.
          • Ghiselli G.
          • Forte T.M.
          • Ordovas J.M.
          • Zech L.A.
          • Brewer Jr., H.B.
          Familial apolipoprotein E deficiency.
          J Clin Invest. 1986; 78 (Dr. Brewer’s comment: Clinical and metabolic characterization of the patient with apo-E deficiency): 1206-1219
          • Fojo S.S.
          • Law S.W.
          • Brewer Jr., H.B.
          The human preproapolipoprotein C-II gene. Complete nucleic acid sequence and genomic organization.
          FEB. 1987; 213 (Dr. Brewer’s comment: Complete genomic sequence of the C-II apolipoprotein): 221-226
          • Fairwell T.
          • Hospattankar A.V.
          • Brewer Jr., H.B.
          • Khan S.A.
          Human plasma apolipoprotein C-II.
          Proc Natl Acad Sci USA. 1987; 84 (Dr. Brewer’s comment: Total synthesis and characterization of a human plasma apolipoprotein, apo-C-II): 4796-4800
          • Hospattankar A.V.
          • Higuchi K.
          • Law S.W.
          • Meglin N.
          • Brewer Jr., H.B.
          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
          • Tennyson G.E.
          • Sabatos C.A.
          • Higuchi K.
          • Meglin N.
          • Brewer Jr., H.B.
          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
          • Beg O.U.
          • Meng M.S.
          • Skarlatos S.I.
          • Previato L.
          • Brunzell J.D.
          • Brewer Jr., H.B.
          • Fojo S.S.
          Lipoprotein lipaseBethesda.
          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
          • Schaefer J.R.
          • Rader D.J.
          • Gregg R.E.
          • Fairwell T.
          • Zech L.A.
          • Kindt M.R.
          • Benson M.D.
          • Brewer Jr, H.B.
          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)
          • Nichols W.C.
          • Gregg R.E.
          • Brewer Jr., H.B.
          • Benson M.D.
          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
          • Santamarina-Fojo S.
          • Brewer Jr., H.B.
          The familial hyperchylomicronemia syndrome.
          JAMA. 1991; 265 (Dr. Brewer’s comment: Review of molecular defects in lipoprotein lipase resulting in hypertriglyceridemia and type I hyperlipidemia): 904-908
          • Rader D.J.
          • Castro G.
          • Zech L.A.
          • Fruchart J.C.
          • Brewer Jr., H.B.
          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
          • Emmerich J.
          • Beg O.U.
          • Peterson J.
          • Previato L.
          • Brunzell J.D.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Klein H.-G.
          • Lohse P.
          • Pritchard P.H.
          • Bojanovski D.
          • Schmidt H.
          • Brewer Jr., H.B.
          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
          • Dugi K.A.
          • Dichek H.L.
          • Talley G.D.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          Human lipoprotein lipase.
          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
          • Rader D.J.
          • Gregg R.E.
          • Meng M.S.
          • Schaefer J.R.
          • Zech L.Z.
          • Benson M.D.
          • Brewer Jr., H.B.
          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
          • Mautner S.L.
          • Sanchez J.A.
          • Rader D.J.
          • Mautner G.C.
          • Ferrans V.J.
          • Fredickson D.S.
          • Brewer Jr., H.B.
          • Roberts W.C.
          The heart in Tangier Disease.
          Am J Clin Pathol. 1992; 98 (Dr. Brewer’s comment: Detailed analysis of the coronary atherosclerosis in a patient with Tangier disease): 191-198
          • Klein H.-G.
          • Santamarina-Fojo S.
          • Duverger N.
          • Clerc M.
          • Dumon M.-F.
          • Albers J.J.
          • Marcovina S.
          • Brewer Jr., H.B.
          Fish eye syndrome.
          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
          • Roma P.
          • Gregg R.E.
          • Meng M.S.
          • Ronan R.
          • Zech L.A.
          • Franceschini G.
          • Sirtori C.R.
          • Brewer Jr., H.B.
          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
          • Rader D.J.
          • Schaefer J.R.
          • Lohse P.
          • Ikewaki K.
          • Thomas F.
          • Harris W.A.
          • Zech L.A.
          • Dujovne C.A.
          • Brewer Jr., H.B.
          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
          • Ikewaki K.
          • Rader D.J.
          • Sakamoto T.
          • Nishiwaki M.
          • Wakimoto N.
          • Schaefer J.R.
          • Ishikawa T.
          • Fairwell T.
          • Zech L.A.
          • Nakamura H.
          • Nagano M.
          • Brewer Jr., H.B.
          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
          • Rader D.J.
          • Ikweaki K.
          • Duverger N.
          • Schmidt H.
          • Pritchard H.
          • Frohlich J.
          • Clerc M.
          • Dumon M.-F.
          • Fairwell T.
          • Zech L.A.
          • Santamarina-Fogo
          • Brewer Jr., H.B.
          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
          • Duverger N.
          • Rader D.
          • Ikewaki K.
          • Nishiwaki M.
          • Sakamoto T.
          • Ishikawa T.
          • Nagano M.
          • Nakamura H.
          • Brewer Jr., H.B.
          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
          • Vaisman B.L.
          • Klein H.-G.
          • Rouis M.
          • Berard A.
          • Kindt M.R.
          • Talley G.D.
          • Meyn S.M.
          • Hoyt Jr., R.F.
          • Marcovina S.M.
          • Albers J.J.
          • Hoeg J.M.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Kashyap V.S.
          • Santamarina-Fojo S.
          • Brown D.R.
          • Parrott C.L.
          • Applebaum-Bowden D.
          • Meyn S.
          • Talley G.
          • Paigen B.
          • Maeda N.
          • Brewer Jr., H.B.
          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
          • Ikewaki K.
          • Nishiwaki M.
          • Sakamoto T.
          • Ishikawa T.
          • Fairwell T.
          • Zech L.A.
          • Nagano M.
          • Nakamura H.
          • Brewer Jr., H.B.
          • Rader D.J.
          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
          • Applebaum-Bowden D.
          • Kobayashi J.
          • Kashyap V.S.
          • Brown D.R.
          • Berard A.
          • Meyn S.
          • Parrott C.
          • Maeda N.
          • Shamburek R.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Hoeg J.M.
          • Vaisman B.L.
          • Demosky S.J.
          • Meyn S.M.
          • Talley G.D.
          • Hoyt R.F.
          • Feldman S.
          • Berard A.M.
          • Sakai N.
          • Wood D.
          • Brousseau M.E.
          • Marcovina S.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Brousseau M.E.
          • Santamarina-Fojo S.
          • Zech L.A.
          • Berard A.M.
          • Vaisman B.L.
          • Meyn S.M.
          • Powell D.
          • Brewer Jr., H.B.
          • Hoeg J.M.
          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
          • Hoeg J.M.
          • Santamarina-Fojo S.
          • Bérard A.M.
          • Cornhill J.F.
          • Herderick E.E.
          • Feldman S.H.
          • Haudenschild C.C.
          • Vaisman B.L.
          • Hoyt Jr., R.F.
          • Demosky Jr., S.J.
          • Kauffman R.D.
          • Hazel C.M.
          • Marcovina S.M.
          • Brewer Jr., H.B.
          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
          • Sakai N.
          • Vaisman B.L.
          • Koch
          • Hoyt R.F.
          • Meyn S.M.
          • Talley G.D.
          • Paiz J.A.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          Targeted disruption of the mouse lecithin.
          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
          • Foger B.
          • Santamarina-Fojo S.
          • Shamburek R.D.
          • Parrot C.L.
          • Talley G.D.
          • Brewer Jr., H.B.
          Plasma phospholipid transfer protein.
          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
          • Remaley A.T.
          • Shumaker U.K.
          • Stonik J.A.
          • Farsi B.D.
          • Nazih H.
          • Brewer Jr., H.B.
          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
          • Hammad S.M.
          • Stefansson S.
          • Twal W.O.
          • Drake C.J.
          • Fleming P.
          • Remaley A.
          • Brewer Jr., H.B.
          • Argraves W.S.
          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)
          • Rust S.
          • Rosier M.
          • Funke H.
          • Real J.
          • Amoura Z.
          • Piette J.C.
          • Deleuze J.F.
          • Brewer Jr., H.B.
          • Duverger N.
          • Denefle P.
          • Assmann G.
          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
          • Remaley A.T.
          • Rosier M.
          • Knapper C.
          • Peterson K.M.
          • Koch C.
          • Duverger N.
          • Assmann G.
          • Dinger M.
          • Dean M.
          • Santamarina-Fojo S.
          • Fredrickson D.S.
          • Denefle P.
          • Brewer Jr., H.B.
          Human ATP-binding cassette transporter 1 (ABC1).
          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
          • Foger B.
          • Chase M.
          • Amar M.J.
          • Vaisman B.L.
          • Shamburek R.D.
          • Paigen B.
          • Fruchart-Najib J.
          • Paiz J.A.
          • Koch C.A.
          • Hoyt R.F.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Dugi K.A.
          • Amar M.J.A.
          • Haudenschild C.C.
          • Shamburek R.D.
          • Bensadoun A.
          • Hoyt Jr, R.F.
          • Fruchart-Najib J.
          • Madj Z.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Santamarina-Fojo S.
          • Lambert G.
          • Hoeg J.M.
          • Brewer Jr., H.B.
          Lecithin Cholesterol Acyltransferase (LCAT).
          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
          • Lambert G.
          • Sakai N.
          • Vaisman B.L.
          • Neufeld E.B.
          • Chan C.-C.
          • Paigen B.
          • Lupia E.
          • Thomas A.
          • Striker L.J.
          • Blanchette-Mackie J.
          • Costello R.
          • Brewer Jr., H.B.
          • Csako G.
          • Striker G.E.
          • Santamarina-Fojo S.
          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
          • Vaisman B.L.
          • Lambert G.
          • Amar M.
          • Joyce C.
          • Ito T.
          • Shamburek R.D.
          • Cain W.J.
          • Fruchart-Najib J.
          • Neufeld E.D.
          • Remaley A.T.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice.
          J Clin Invest. 2001; 108 (Dr. Brewer’s comment: First description that overexpression of the ABCA1 transporter resulted in high HDL levels): 303-309
          • Neufeld E.B.
          • Remaley A.T.
          • Demosky S.J.
          • Stonik J.A.
          • Cooney A.M.
          • Comly M.
          • Dwyer N.K.
          • Zhang M.
          • Blanchette-Mackie J.
          • Santamarina-Fojo S.
          • Brewer Jr., H.B.
          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
          • Santamarina-Fojo S.
          • Remaley A.T.
          • Neufeld E.B.
          • Brewer Jr., H.B.
          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
          • Remaley A.T.
          • Stonik J.A.
          • Demosky S.J.
          • Neufeld E.B.
          • Bocharov A.V.
          • Vishnyakova T.G.
          • Eggerman T.L.
          • Patterson A.P.
          • Duverger N.J.
          • Santamarina-Fojo S.
          • Brewer Jr., H.B.
          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
          • Berard A.M.
          • Clerc M.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Joyce C.W.
          • Amar M.J.A.
          • Lambert G.
          • Vaisman B.L.
          • Paigen B.
          • Najib-Fruchart J.
          • Parks J.S.
          • Hoyt Jr, R.F.
          • Neufeld E.D.
          • Remaley A.T.
          • Fredrickson D.S.
          • Brewer Jr., H.B.
          • Santamarina-Fojo S.
          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
          • Neufeld E.B.
          • Demosky Jr., S.J.
          • Stonik J.A.
          • Combs C.
          • Remaley A.T.
          • Duverger N.
          • Santamarina-Fojo S.
          • Brewer Jr., H.B.
          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
          • Hannuksela M.L.
          • Brousseau M.E.
          • Meyn S.M.
          • Nazih H.
          • Bader G.
          • Shamburek R.D.
          • Alaupovic P.
          • Brewer Jr., H.B.
          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
          • Basso F.
          • Freeman L.
          • Knapper C.
          • Remaley A.
          • Stonik J.
          • Tansey T.
          • Amar M.J.A.
          • Fruchart-Najib J.
          • Dugerger N.
          • Santamarina-Fojo S.
          • Brewer Jr., H.B.
          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
          • Remaley A.T.
          • Thomas F.
          • Stonik J.A.
          • Demosky S.J.
          • Bark S.E.
          • Neufeld E.B.
          • Bocharov A.V.
          • Vishnyakova T.G.
          • Patterson A.P.
          • Eggerman T.L.
          • Santamarina-Fojo S.
          • Brewer Jr., H.B.
          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
          • Neufeld E.B.
          • Stonik J.A.
          • Demosky S.J.
          • Knapper C.L.
          • Combs C.A.
          • Cooney A.
          • Comly M.
          • Dwyer N.
          • Blanchette-Mackie J.
          • Remaley A.T.
          • Santamarina-Fojo S.
          • Brewer Jr., H.B.
          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
          • Brewer Jr., H.B.
          High-density lipoproteins.
          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
          • Brewer Jr., H.B.
          Increasing HDL cholesterol levels.
          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
          • Stonik J.A.
          • Remaley A.T.
          • Demosky S.J.
          • Neufeld E.B.
          • Bocharov A.
          • Brewer Jr., H.B.
          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
          • Brewer Jr., H.B.
          • Remaley A.T.
          • Neufeld E.B.
          • Basso F.
          • Joyce C.
          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