Macrophage-derived foam cells accumulate in atherosclerotic lesions and throughout the body in some forms of hypertriglyceridemia (HTG). Uptake of abnormal triglyceride-rich lipoproteins (abTGRLP) by a macrophage receptor(R) distinct from the LDL R and the acetyl LDL R that the investigators recently described in murine macrophages and human monocyte-macrophages may be responsible for foam cell formation in HTG humans. Moreover, this R also binds oxidized LDL with high affinity, suggesting that this pathway may be important in foam cell formation in hypercholesterolemia as well as in HTG. The goals of the proposed work are (1) to isolate and characterize the human monocyte-macrophage receptor for abnormal TGRLP and (2) to identify the binding determinants present in abTGRLP that are absent or masked in TGRLP from normal subjects and to determine if lowering plasma TG levels in HTG subjects normalizes the TGRLP. The human monocytic line THP-1 will be used as a source for purification of plasma membrane binding proteins identified as likely receptor candidates for partial microsequencing and production of antibodies against the receptor. Molecular biological approaches will identify receptor complementary DNA clones to elucidate receptor primary structure and to characterize cellular mRNA. Competitive and direct cell binding and ligand blotting studies with native and modified VLDL, model VLDL, and mapped monoclonal antibodies against apoB will identify binding determinants. These studies should provide basic cellular and molecular mechanisms pertinent to foam cell formation in humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL044480-05
Application #
2221506
Study Section
Metabolism Study Section (MET)
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Haraguchi, Go; Kobayashi, Yasushi; Brown, Matthew L et al. (2003) PPAR(alpha) and PPAR(gamma) activators suppress the monocyte-macrophage apoB-48 receptor. J Lipid Res 44:1224-31
Brown, Matthew L; Yui, Katsumasa; Smith, Jonathan D et al. (2002) The murine macrophage apoB-48 receptor gene (Apob-48r): homology to the human receptor. J Lipid Res 43:1181-91
Datta, G; Garber, D W; Chung, B H et al. (2001) Cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo. J Lipid Res 42:959-66
Brown, M L; Ramprasad, M P; Umeda, P K et al. (2000) A macrophage receptor for apolipoprotein B48: cloning, expression, and atherosclerosis. Proc Natl Acad Sci U S A 97:7488-93
Datta, G; Chaddha, M; Garber, D W et al. (2000) The receptor binding domain of apolipoprotein E, linked to a model class A amphipathic helix, enhances internalization and degradation of LDL by fibroblasts. Biochemistry 39:213-20
Bradley, W A; Brown, M L; Ramprasad, M P et al. (1999) Antipeptide antibodies reveal interrelationships of MBP 200 and MBP 235: unique apoB-specific receptors for triglyceride-rich lipoproteins on human monocyte-macrophages. J Lipid Res 40:744-52
Gianturco, S H; Ramprasad, M P; Song, R et al. (1998) Apolipoprotein B-48 or its apolipoprotein B-100 equivalent mediates the binding of triglyceride-rich lipoproteins to their unique human monocyte-macrophage receptor. Arterioscler Thromb Vasc Biol 18:968-76
Li, X N; Grenett, H E; Benza, R L et al. (1997) Genotype-specific transcriptional regulation of PAI-1 expression by hypertriglyceridemic VLDL and Lp(a) in cultured human endothelial cells. Arterioscler Thromb Vasc Biol 17:3215-23
Ramprasad, M P; Li, R; Bradley, W A et al. (1995) Human THP-1 monocyte-macrophage membrane binding proteins: distinct receptor(s) for triglyceride-rich lipoproteins. Biochemistry 34:9126-35
Ramprasad, M P; Li, R; Gianturco, S H et al. (1995) Purification of the human THP-1 monocyte-macrophage triglyceride-rich lipoprotein receptor. Biochem Biophys Res Commun 210:491-7

Showing the most recent 10 out of 14 publications