H B Brewer

National Heart, Lung, and Blood Institute, Maryland, United States

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Publications (325)2138.23 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Lecithin-cholesterol acyltransferase (LCAT), a key enzyme in high-density lipoprotein (HDL) metabolism, has been proposed to have atheroprotective properties by promoting reverse cholesterol transport. Overexpression of LCAT in various animal models, however, has led to conflicting results on its overall effect on lipoproteins and atherosclerosis. In this study, the effect of overexpression of LCAT in nonhuman primates on lipoprotein metabolism is examined. Human LCAT was expressed with adenovirus in squirrel monkeys (n = 8), resulting on day 4 in a 22-fold increase of LCAT activity (257 +/- 23 vs 5618 +/- 799 nmol mL(-1) h(-1), P < .0001). At its peak, LCAT was found to nearly double the level of HDL cholesterol from baseline (113 +/- 7 vs 260 +/- 24 mg/dL, P < .01). High-density lipoprotein formed after treatment with the adenovirus was larger in size, as assessed by fast protein liquid chromatography (FPLC) analysis. By kinetic studies, it was determined that there was a decrease in apolipoprotein (Apo) A-I resident time (0.373 +/- 0.027 vs 0.685 +/- 0.045 d(-1), P < .0001) and almost a doubling in the ApoA-I synthetic rate (22 +/- 2 vs 41 +/- 3 mg kg(-1) d(-1), P < .0001), but no overall change in ApoA-I levels. In addition, increased expression of LCAT was associated with a 37% reduction of ApoB levels (12 +/- 1 vs 19 +/- 1 mg/dL, P < .05) due to increased low-density lipoprotein catabolism (fractional catabolic rate = 1.7 +/- 0.1 d(-1) in controls vs 4.2 +/- 0.3 d(-1) in LCAT-treated group, P < .05). In summary, overexpression of LCAT in nonhuman primates leads to an antiatherogenic lipoprotein profile by increasing HDL cholesterol and lowering ApoB, thus making LCAT a potential drug target for reducing atherosclerosis.
    Metabolism: clinical and experimental 04/2009; 58(4):568-75. · 3.10 Impact Factor
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2006; 7(3):320-320.
  • Atherosclerosis Supplements - ATHEROSCLER SUPPL. 01/2006; 7(3):482-482.
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    Ref. No: 6,846,636, Year: 01/2005
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    ABSTRACT: The discovery of the role of the ATP-binding cassette transporter A1 (ABCA1) in mediating apolipoprotein A-I-mediated efflux has led to a dramatic increase in our knowledge of the molecular mechanisms involved in cholesterol efflux and cellular metabolism. In this review, we discuss several aspects of ABCA1 regulation including i) transcriptional regulation, ii) substrate specificity and availability, iii) accessory proteins, iv) acceptor specificity and availability, and v) protein trafficking. The majority of studies of ABCA1 regulation to date have focused on the identification of promoter elements that determine ABCA1 gene transcription. Here we also review the potential functional role of ABCA1 in reverse cholesterol transport. Given the key role that ABCA1 plays in cholesterol homeostasis, it is likely that there are multiple mechanisms for controlling the overall transporter activity of ABCA1.
    The Journal of Lipid Research 10/2001; 42(9):1339-45. · 4.39 Impact Factor
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    ABSTRACT: Sitosterolemia is a rare autosomal recessive disorder characterized by (a) intestinal hyperabsorption of all sterols, including cholesterol and plant and shellfish sterols, and (b) impaired ability to excrete sterols into bile. Patients with this disease have expanded body pools of cholesterol and very elevated plasma plant-sterol species and frequently develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. In previous studies, we have mapped the STSL locus to human chromosome 2p21. Recently, we reported that a novel member of the ABC-transporter family, named "sterolin-1" and encoded by ABCG5, is mutated in 9 unrelated families with sitosterolemia; in the remaining 25 families, no mutations in sterolin-1 could be identified. We identified another ABC transporter, located <400 bp upstream of sterolin-1, in the opposite orientation. Mutational analyses revealed that this highly homologous protein, termed "sterolin-2" and encoded by ABCG8, is mutated in the remaining pedigrees. Thus, two highly homologous genes, located in a head-to-head configuration on chromosome 2p21, are involved as causes of sitosterolemia. These studies indicate that both sterolin-1 and sterolin-2 are indispensable for the regulation of sterol absorption and excretion. Identification of sterolin-1 and sterolin-2 as critical players in the regulation of dietary-sterol absorption and excretion identifies a new pathway of sterol transport.
    The American Journal of Human Genetics 09/2001; 69(2):278-90. · 11.20 Impact Factor
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    ABSTRACT: To evaluate the biochemical and molecular mechanisms leading to glomerulosclerosis and the variable development of atherosclerosis in patients with familial lecithin cholesterol acyl transferase (LCAT) deficiency, we generated LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E KO, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transfer protein transgenic mice. LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased red blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipoprotein X and developed proteinuria and glomerulosclerosis characterized by mesangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduced the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and non-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and cholesteryl ester transfer protein-Tg mice. Transcriptome and Western blot analysis demonstrated up-regulation of hepatic LDLr and apoE expression in LCAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantly reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our studies indicate (i) that the plasma levels of apoB containing lipoproteins rather than HDL may determine the atherogenic risk of patients with hypoalphalipoproteinemia due to LCAT deficiency and (ii) a potential etiological role for lipoproteins X in the development of glomerulosclerosis in LCAT deficiency. The availability of LCAT-KO mice characterized by lipid, hematologic, and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.
    Journal of Biological Chemistry 06/2001; 276(18):15090-8. · 4.65 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.
    Nature Medicine 02/2001; 7(1):53-8. · 22.86 Impact Factor
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    ABSTRACT: Erdheim-Chester disease (ECD) is a rare multisystem histiocytosis syndrome of unknown cause that usually affects adults. Histiocytic infiltration of multiple end organs produces bone pain, xanthelasma and xanthoma, exophthalmos, diabetes insipidus, and interstitial lung disease. Differential diagnosis includes Langerhans cell histiocytosis, metabolic disorders, malignancy, and sarcoidosis. ECD can be diagnosed using a combination of clinical and histopathologic findings. Sites of involvement include lung, bone, skin, retroorbital tissue, central nervous system, pituitary gland, retroperitoneum, and pericardium. Symmetrical long bone pain with associated osteosclerotic lesions, xanthomas around the eyelids, exophthalmos, and/or diabetes insipidus suggest ECD. Approximately 35% of patients have associated lung involvement, characterized by interstitial accumulations of histiocytic cells and fibrosis in a predominantly perilymphangitic and subpleural pattern. This pattern distinguishes ECD from other histiocytic disorders involving the lung. The diagnosis is confirmed by tissue biopsies that contain histiocytes with non-Langerhans cell features. In general, the clinical course of patients with this disease varies, and the prognosis can be poor despite treatment. Clinical trials for treatment of ECD have not been conducted and treatment is based on anecdotal experience.
    The American Journal of the Medical Sciences 02/2001; 321(1):66-75. · 1.33 Impact Factor
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    ABSTRACT: The thoracic aorta is an important site of atherosclerotic disease in patients with homozygous familial hypercholesterolemia (HFH). Thoracic aortic atherosclerosis in patients with HFH was assessed with contrast-enhanced MR angiograms using exoscopic and endoscopic virtual angioscopy reconstructions and maximum intensity projections (MIPs). Contrast-enhanced MR angiograms of the thoracic aorta of 15 patients with HFH and 8 normal volunteers were obtained. Perspective surface reconstructions of the MR angiograms including virtual angioscopy views were evaluated by three radiologists blinded to the diagnosis. Thoracic wall irregularity was depicted on 8 of 15 (53%) patient scans and only 1 of 8 (13%) normal subject scans using surface reconstructions. Wall irregularity scores of patients with HFH were significantly increased compared with controls (2.0 +/- 0.9 vs. 1.0 +/- 0.6; p = 0.008). There was excellent interobserver agreement (weighted kappa = 0.82 +/- 0.12). Virtual endoscopy views added diagnostic confidence compared with exoscopic surface renderings alone. MIP reconstructions were unable to depict wall irregularity. MR angiography with virtual angioscopy of the thoracic aorta depicts nonstenotic wall irregularity of thoracic aortic atherosclerosis in patients with HFH. This may be important for assessing disease progression and response to treatment and may be generalizable to routine (non-HFH) atherosclerosis.
    Journal of Computer Assisted Tomography 01/2001; 25(3):371-7. · 1.58 Impact Factor
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    ABSTRACT: The ABCA1 gene, a member of the ATP-binding cassette A (ABCA1) transporter superfamily, encodes a membrane protein that facilitates the cellular efflux of cholesterol and phospholipids. Mutations in ABCA1 lead to familial high density lipoprotein deficiency and Tangier disease. We report the complete human ABCA1 gene sequence, including 1,453 bp of the promoter, 146,581 bp of introns and exons, and 1 kb of the 3' flanking region. The ABCA1 gene spans 149 kb and comprises 50 exons. Sixty-two repetitive Alu sequences were identified in introns 1-49. The transcription start site is 315 bp upstream of a newly identified initiation methionine codon and encodes an ORF of 6,783 bp. Thus, the ABCA1 protein is comprised of 2,261 aa. Analysis of the 1,453 bp 5' upstream of the transcriptional start site reveals multiple binding sites for transcription factors with roles in lipid metabolism. Comparative analysis of the mouse and human ABCA1 promoter sequences identified specific regulatory elements, which are evolutionarily conserved. The human ABCA1 promoter fragment -200 to -80 bp that contains binding motifs for SP1, SP3, E-box, and AP1 modulates cellular cholesterol and cAMP regulation of ABCA1 gene expression. These combined findings provide insights into ABCA1-mediated regulation of cellular cholesterol metabolism and will facilitate the identification of new pharmacologic agents for the treatment of atherosclerosis in humans.
    Proceedings of the National Academy of Sciences 08/2000; 97(14):7987-92. · 9.81 Impact Factor
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    ABSTRACT: In the past several years significant advances have been made in our understanding of lecithin-cholesterol acyltransferase (LCAT) function. LCAT beneficially alters the plasma concentrations of apolipoprotein B-containing lipoproteins, as well as HDL. In addition, its proposed role in facilitating reverse cholesterol transport and modulating atherosclerosis has been demonstrated in vivo. Analysis of LCAT transgenic animals has established the importance of evaluating HDL function, as well as HDL plasma levels, to predict atherogenic risk.
    Current Opinion in Lipidology 07/2000; 11(3):267-75. · 5.84 Impact Factor
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    ABSTRACT: Recent in vitro studies have provided evidence that hepatic lipase (HL) facilitates the selective uptake of HDL cholesteryl esters (CE), but the in vivo physiological relevance of this process has not been demonstrated. To evaluate the role that HL plays in facilitating the selective uptake of HDL-CE in vivo, we studied the metabolism of [(3)H]CEt, (125)I-labeled apolipoprotein (apo) A-I, and (131)I-labeled apoA-II-labeled HDL in HL-deficient mice. Kinetic analysis revealed similar catabolism of (125)I-labeled apoA-I (as well as (131)I-labeled apoA-II) in C57BL controls and HL deficient mice, with fractional catabolic rates (FCR) of 2.17 +/- 0.15 and 2.16 +/- 0.11 d(-)(1) (2.59 +/- 0.14 and 2.67 +/- 0.13 d(-)(1), respectively). In contrast, despite similar hepatic scavenger receptor BI expression, HL-deficient mice had delayed clearance of [(3)H]CEt compared to controls (FCR = 3.66 +/- 0.29 and 4.41 +/- 0.18 d(-)(1), P < 0.05). The hepatic accumulation of [(3)H]CEt in HL-deficient mice (62.3 +/- 2.1% of total) was significantly less than in controls (72.7 +/- 3.0%), while the [(3)H]CEt remaining in the plasma compartment increased (20.7 +/- 1.8% and 12.6 +/- 0.5%) (P < 0.05, all). In summary, HL deficiency does not alter the catabolism of apoA-I and apoA-II but decreases the hepatic uptake and the plasma clearance of HDL-CE. These data establish for the first time an important role for HL in facilitating the selective uptake of HDL-CE in vivo.
    The Journal of Lipid Research 06/2000; 41(5):667-72. · 4.39 Impact Factor
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    ABSTRACT: To investigate the in vivo role that hepatic lipase (HL) plays in HDL metabolism independently of its lipolytic function, recombinant adenovirus (rAdV) expressing native HL, catalytically inactive HL (HL-145G), and luciferase control was injected in HL-deficient mice. At day 4 after infusion of 2 x 10(8) plaque-forming units of rHL-AdV and rHL-145G-AdV, similar plasma concentrations were detected in postheparin plasma (HL=8.4+/-0.8 microg/mL and HL-145G=8.3+/-0.8 microg/mL). Mice expressing HL had significant reductions of cholesterol (-76%), phospholipids (PL; -68%), HDL cholesterol (-79%), apolipoprotein (apo) A-I (-45%), and apoA-II (-59%; P<0.05 for all), whereas mice expressing HL-145G decreased their cholesterol (-49%), PL (-40%), HDL cholesterol (-42%), and apoA-II (-89%; P<0.005 for all) but had no changes in apoA-I. The plasma kinetics of (125)I-labeled apoA-I HDL, (131)I-labeled apoA-II HDL, and [(3)H]cholesteryl ester (CE) HDL revealed that compared with mice expressing luciferase control (fractional catabolic rate [FCR] in d(-1): apoA-I HDL=1.3+/-0.1; apoA-II HDL=2.1+/-0; CE HDL=4.1+/-0.7), both HL and HL-145G enhanced the plasma clearance of CEs and apoA-II present in HDL (apoA-II HDL=5.6+/-0.5 and 4.4+/-0.2; CE HDL=9.3+/-0. 0 and 8.3+/-1.1, respectively), whereas the clearance of apoA-I HDL was enhanced in mice expressing HL (FCR=4.6+/-0.3) but not HL-145G (FCR=1.4+/-0.4). These combined findings demonstrate that both lipolytic and nonlipolytic functions of HL are important for HDL metabolism in vivo. Our study provides, for the first time, in vivo evidence for a role of HL in HDL metabolism independent of lipolysis and provides new insights into the role of HL in facilitating distinct metabolic pathways involved in the catabolism of apoA-I- versus apoA-II-containing HDL.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2000; 20(3):793-800. · 6.34 Impact Factor
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    ABSTRACT: Elevated low density lipoprotein cholesterol (LDL-C) and reduced high density lipoprotein cholesterol (HDL-C) concentrations are independent risk factors for coronary heart disease. We have previously demonstrated that overexpression of an enzyme with a well established role in HDL metabolism, lecithin:cholesterol acyltransferase (LCAT), in New Zealand White rabbits not only raises HDL-C concentrations but reduces those of LDL-C as well, ultimately preventing diet-induced atherosclerosis. In the present study, the human LCAT gene (hLCAT) was introduced into LDL receptor (LDLr)-deficient (Watanabe heritable hyperlipidemic) rabbits to (1) investigate the role of the LDLr pathway in the hLCAT-mediated reductions of LDL-C and (2) determine the influence of hLCAT overexpression on atherosclerosis susceptibility in an animal model of familial hypercholesterolemia. Heterozygosity or homozygosity for the LDLr defect was determined by polymerase chain reaction, and 3 groups of hLCAT-transgenic (hLCAT+) rabbits that differed in LDLr status were established: (1) LDLr wild-type (LDLr+/+), (2) LDLr heterozygotes (LDLr+/-), and (3) LDLr homozygotes (LDLr-/-). Data for hLCAT+ rabbits were compared with those of nontransgenic (hLCAT-) rabbits of the same LDLr status. Plasma HDL-C concentrations were significantly elevated in the hLCAT+ animals of each LDLr status. However, LDL-C levels were significantly reduced only in hLCAT+/LDLr+/+ and hLCAT+/LDLr+/- rabbits but not in hLCAT+/LDLr-/- rabbits (405+/-14 versus 392+/-31 mg/dL). Metabolic studies revealed that the fractional catabolic rate (FCR, d(-1)) of LDL apolipoprotein (apo) B-100 was increased in hLCAT+/LDLr+/+ (26+/-4 versus 5+/-0) and hLCAT+/LDLr+/- (4+/-1 versus 1+/-0) rabbits, whereas the FCR of LDL apoB-100 in both groups of LDLr-/- rabbits was nearly identical (0.16+/-0.02 versus 0.15+/-0.02). Consistently, neither aortic lipid concentrations nor the extent of aortic atherosclerosis was significantly different between hLCAT+/LDLr-/- and hLCAT-/LDLr-/- rabbits. Significant correlations were observed between the percent of aortic atherosclerosis and both LDL-C (r=0.985) and LDL apoB-100 FCR (-0.745), as well as between LDL-C and LDL apoB-100 FCR (-0.866). These data are the first to establish that LCAT modulates LDL metabolism via the LDLr pathway, ultimately influencing atherosclerosis susceptibility. Moreover, LCAT's antiatherogenic effect requires only a single functional LDLr allele, identifying LCAT as an attractive gene therapy candidate for the majority of dyslipoproteinemic patients.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2000; 20(2):450-8. · 6.34 Impact Factor
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    ABSTRACT: Tangier disease (TD) was first discovered nearly 40 years ago in two siblings living on Tangier Island. This autosomal co-dominant condition is characterized in the homozygous state by the absence of HDL-cholesterol (HDL-C) from plasma, hepatosplenomegaly, peripheral neuropathy and frequently premature coronary artery disease (CAD). In heterozygotes, HDL-C levels are about one-half those of normal individuals. Impaired cholesterol efflux from macrophages leads to the presence of foam cells throughout the body, which may explain the increased risk of coronary heart disease in some TD families. We report here refining of our previous linkage of the TD gene to a 1-cM region between markers D9S271 and D9S1866 on chromosome 9q31, in which we found the gene encoding human ATP cassette-binding transporter 1 (ABC1). We also found a change in ABC1 expression level on cholesterol loading of phorbol ester-treated THP1 macrophages, substantiating the role of ABC1 in cholesterol efflux. We cloned the full-length cDNA and sequenced the gene in two unrelated families with four TD homozygotes. In the first pedigree, a 1-bp deletion in exon 13, resulting in truncation of the predicted protein to approximately one-fourth of its normal size, co-segregated with the disease phenotype. An in-frame insertion-deletion in exon 12 was found in the second family. Our findings indicate that defects in ABC1, encoding a member of the ABC transporter superfamily, are the cause of TD.
    Nature Genetics 09/1999; 22(4):352-5. · 35.21 Impact Factor
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    ABSTRACT: Receptors that endocytose high-density lipoproteins (HDL) have been elusive. Here yolk-sac endoderm-like cells were used to identify an endocytic receptor for HDL. The receptor was isolated by HDL affinity chromatography and identified as cubilin, the recently described endocytic receptor for intrinsic factor-vitamin B(12). Cubilin antibodies inhibit HDL endocytosis by the endoderm-like cells and in mouse embryo yolk-sac endoderm, a prominent site of cubilin expression. Cubilin-mediated HDL endocytosis is inhibitable by HDL(2), HDL(3), apolipoprotein (apo)A-I, apoA-II, apoE, and RAP, but not by low-density lipoprotein (LDL), oxidized LDL, VLDL, apoC-I, apoC-III, or heparin. These findings, coupled with the fact that cubilin is expressed in kidney proximal tubules, suggest a role for this receptor in embryonic acquisition of maternal HDL and renal catabolism of filterable forms of HDL.
    Proceedings of the National Academy of Sciences 09/1999; 96(18):10158-63. · 9.81 Impact Factor
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    ABSTRACT: Hepatic lipase (HL) plays a major role in high-density lipoprotein (HDL) metabolism both as a lipolytic enzyme and as a ligand. To investigate whether HL enhances the uptake of HDL-cholesteryl ester (CE) via the newly described scavenger receptor BI (SR-BI), we measured the effects of expressing HL and SR-BI on HDL-cell association as well as uptake of 125I-labeled apoA-I and [3H]CE-HDL, by embryonal kidney 293 cells. As expected, HDL cell association and CE selective uptake were increased in SR-BI transfected cells by 2- and 4-fold, respectively, compared to controls (P < 0.001). Cells transfected with HL alone or in combination with SR-BI expressed similar amounts of HL, 20% of which was bound to cell surface proteoglycans. HL alone increased HDL cell association by 2-fold but had no effect on HDL-CE uptake in 293 cells. However, in cells expressing SR-BI, HL further enhanced the selective uptake of CE from HDL by 3-fold (P < 0.001). To determine whether the lipolytic and/or ligand function of HL are required in this process, we generated a catalytically inactive form of HL (HL-145G). Cells co-transfected with HL-145G and SR-BI increased their HDL cell association and HDL-CE selective uptake by 1.4-fold compared to cells expressing SR-BI only (P < 0.03). Heparin abolished the effect of HL-145G on SR-BI-mediated HDL-CE selective uptake.Thus, the enhanced uptake of HDL-CE by HL is mediated by both its ligand role, which requires interaction with proteoglycans, and by lipolysis with subsequent HDL particle remodeling. These results establish HL as a major modulator of SR-BI mediated selective uptake of HDL-CE.
    The Journal of Lipid Research 07/1999; 40(7):1294-303. · 4.39 Impact Factor
  • H B Brewer
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    ABSTRACT: There is a growing body of evidence from epidemiologic, clinical, and laboratory data that indicates that elevated triglyceride levels are an independent risk factor for cardiovascular disease. Identification and quantification of atherogenic lipoproteins in patients with hypertriglyceridemia are important steps in the prevention of cardiovascular disease. Increased levels of apoC-III, apoC-I, or apoA-II on the apoB-containing lipoproteins may alter lipoprotein metabolism and result in the accumulation of atherogenic remnants. Hypertriglyceridemic patients at risk for cardiovascular disease often develop a lipoprotein profile characterized by elevated triglyceride, dense LDL, and low HDL cholesterol. Understanding that each of these factors contributes separately to the patient's risk of cardiovascular disease can help physicians provide patients with more effective risk-reduction programs for cardiovascular disease.
    The American Journal of Cardiology 06/1999; 83(9B):3F-12F. · 3.21 Impact Factor
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    ABSTRACT: We have investigated the role of hepatic lipase (HL) in remnant lipoprotein metabolism independent of lipolysis by using recombinant adenovirus to express native and catalytically inactive HL (HL-145G) in apolipoprotein (apo)E-deficient mice characterized by increased plasma concentrations of apoB-48-containing remnants. In the absence of apoE, the mechanisms by which apoB-48-containing remnants are taken up by either low density lipoprotein (LDL)-receptor or LDL-receptor-related protein (LRP) remain unclear. Overexpression of either native or catalytically inactive HL in apoE-deficient mice led to similar reductions (P > 0.5) in the plasma concentrations of cholesterol (41% and 53%) and non high density lipoprotein (HDL)-cholesterol (41% and 56%) indicating that even in the absence of lipolysis, HL can partially compensate for the absence of apoE in this animal model. Although the clearance of [3H]cholesteryl ether from VLDL was significantly increased (approximately 2-fold; P < 0. 02) in mice expressing native or inactive HL compared to luciferase controls, the fractional catabolic rates (FCR) of [125I-labeled] apoB- very low density lipoprotein (VLDL) in all three groups of mice were similar (P > 0.4, all) indicating selective cholesterol uptake. Hepatic uptake of [3H]cholesteryl ether from VLDL was greater in mice expressing either native HL (87%) or inactive HL-145G (72%) compared to luciferase controls (56%). Our combined findings are consistent with a role for HL in mediating the selective uptake of cholesterol from remnant lipoproteins in apoE-deficient mice, independent of lipolysis. These studies support the concept that hepatic lipase (HL) may serve as a ligand that mediates the interaction between remnant lipoproteins and cell surface receptors and/or proteoglycans. We hypothesize that one of these pathways may involve the interaction of HL with cell surface receptors, such as scavenger receptor (SR)-BI, that mediate the selective uptake of cholesteryl esters.
    The Journal of Lipid Research 01/1999; 39(12):2436-42. · 4.39 Impact Factor

Publication Stats

11k Citations
2,138.23 Total Impact Points

Institutions

  • 1972–2001
    • National Heart, Lung, and Blood Institute
      • Hematology Branch
      Maryland, United States
  • 2000
    • Institut Pasteur de Lille
      Lille, Nord-Pas-de-Calais, France
  • 1968–2000
    • National Institutes of Health
      • • Center for Clinical Research
      • • Molecular Targets Laboratory
      Maryland, United States
  • 1999
    • Cornell University
      Ithaca, New York, United States
  • 1994
    • University of Delaware
      Delaware, United States
  • 1992
    • University of Hamburg
      • Department of Internal Medicine II and Clinic (Oncology Center)
      Hamburg, Hamburg, Germany
  • 1985–1987
    • University of Texas Health Science Center at San Antonio
      • Department of Cellular and Structural Biology
      San Antonio, TX, United States
    • University of Alabama at Birmingham
      • Department of Pathology
      Birmingham, AL, United States
  • 1977
    • University of North Carolina at Chapel Hill
      • Department of Medicine
      Chapel Hill, NC, United States
  • 1974
    • University of Minnesota Rochester
      Rochester, Minnesota, United States