The monocyte/macrophage is the precursor of many or most of the foam cells in early atherosclerotic lesions. The proposed studies are designed to enhance our understanding of mechanisms by which these cells take up lipids and mechanisms by which they mobilize stored triglycerides and cholesterol esters. Recent studies in this laboratory demonstrated a high level of neutral triglyceride lipase in macrophages. We propose to explore the regulation of this enzyme and the relation of its activity to observed rates of triglyceride mobilization from previously fat-loaded cells (incubated with fatty acid-albumin or very low density lipoprotein). Parallel studies will address the role of a recently described neutral cholesterol esterase in controlling the build-up of cholesterol ester stores. The activity of this enzyme can be modulated by cyclic AMP-dependent protein kinase. We propose to test whether the activation or responsiveness to activation of the enzyme varies with exposure to hormones, or agents that modulate macrophage functions, state of activation and differentiation of the macrophage or degree of lipid-loading. Macrophages secrete lipoprotein lipase and this has been shown to facilitate uptake of chylomicrons and very low density lipoproteins. Whether its secretion is regulated by insulin and other factors regulating lipoprotein lipase activity in other tissues remains to be determined. We will measure its secretion again as a function of macrophage activation and differentiation. The possibility that dysfunction of the macrophage in diabetic patients may explain their premature atherosclerosis in the absence of hyperlipidemia will be pursued. Macrophages prepared from diabetic animals will be compared with normal macrophages with respect to lipid and lipoprotein metabolism; macrophages from normal animals will be exposed to hormones and metabolites such as those found in diabetics to determine effects on lipoprotein uptake and lipid mobilization. Finally, we will try to test, using perfused segments of aorta, the extent to which triglyceride-rich lipoproteins are taken up by foam cells in early atherosclerotic lesions and the extent to which macrophage lipoprotein lipase is involved in the process. A better understanding of the mechanisms involved in foam cell formations could uncover new methods for intervention.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL034724-02
Application #
3347946
Study Section
Metabolism Study Section (MET)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ziolo, M T; Katoh, H; Bers, D M (2001) Positive and negative effects of nitric oxide on Ca(2+) sparks: influence of beta-adrenergic stimulation. Am J Physiol Heart Circ Physiol 281:H2295-303
Khoo, J C; Miller, E; Pio, F et al. (1992) Monoclonal antibodies against LDL further enhance macrophage uptake of LDL aggregates. Arterioscler Thromb 12:1258-66
Rosenfeld, M E; Khoo, J C; Miller, E et al. (1991) Macrophage-derived foam cells freshly isolated from rabbit atherosclerotic lesions degrade modified lipoproteins, promote oxidation of low-density lipoproteins, and contain oxidation-specific lipid-protein adducts. J Clin Invest 87:90-9
Parthasarathy, S; Khoo, J C; Miller, E et al. (1990) Low density lipoprotein rich in oleic acid is protected against oxidative modification: implications for dietary prevention of atherosclerosis. Proc Natl Acad Sci U S A 87:3894-8
Khoo, J C; Miller, E; McLoughlin, P et al. (1990) Prevention of low density lipoprotein aggregation by high density lipoprotein or apolipoprotein A-I. J Lipid Res 31:645-52
Goldberg, D I; Khoo, J C (1990) Stimulation of a neutral cholesteryl ester hydrolase by cAMP system in P388D1 macrophages. Biochim Biophys Acta 1042:132-7
Khoo, J C; Miller, E; McLoughlin, P et al. (1989) Cholesterol esterification as a limiting factor in accumulation of cell cholesterol: a comparison of two J774 macrophage cell lines. Biochim Biophys Acta 1012:215-7
Khoo, J C; Miller, E; McLoughlin, P et al. (1988) Enhanced macrophage uptake of low density lipoprotein after self-aggregation. Arteriosclerosis 8:348-58
Goldberg, D I; Khoo, J C (1988) Secretion of the lysosomal acid triacylglycerol hydrolase precursor by J774 macrophages. Biochim Biophys Acta 960:200-9
Goldberg, D I; Khoo, J C (1987) Regulation of lipoprotein lipase secretion by mouse peritoneal macrophages. Biochem Biophys Res Commun 142:1-6

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