The effects of cyclic imides on lipoprotein receptor binding and degradation of rat and human cells and effects on regulatory enzymes of lipid metabolism.
A series of cyclic imides, which possess a bulkier N-ring structure than phthalimide and saccharin, were shown to suppress LDL receptor binding, internalization and degradation of isolated rat hepatocytes, foam cells, human fibroblasts and mouse macrophages. The HDL receptor binding and internalization was accelerated in hepatocytes but not in other tissue types. In general, the HDL receptor activity and degradation was reduced by the cyclic imides. The in vivo studies with selected cyclic imides supported this finding in that 125I-LDL was not cleared from serum as rapidly as the control after 14 days of treatment, whereas 125I-HDL was cleared more rapidly by treated rats. The tissue uptake of 125I-LDL amd 125I-HDL was generally reduced in the treated rat tissues after 14 days dosing. These agents did not suppress HMG-CoA reductase activity in any of the tissue cell lines. A correlation existed between lower LDL receptor activity and stimulated HMG-CoA reductase activity in cells. The cyclic imides suppressed the activities of acyl-CoA cholesterol-acyltransferase, sn-glycerol-3-phosphate acyl transferase, and heparin-induced tissue lipoprotein lipase. Neutral cholesterol ester hydrolase activity and protein synthesis were markedly stimulated by the cyclic imides in the aorta foam cells, but not the other cell types.
Wong
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Division of Medicinal Chemistry and Natural Products, School of Pharmacy, University of North Carolina at Chapel Hill 27559-7360.
Williams
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Oswald
B S
BS
Hall
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IH
D000818:Animals; D002478:Cells, Cultured; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology; D007094:Imides / Q000737:chemistry / Q000494:pharmacology*; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D051381:Rats; D011919:Rats, Inbred Strains; D011956:Receptors, Cell Surface / Q000187:drug effects* / Q000378:metabolism; D018110:Receptors, Lipoprotein
D000960:Hypolipidemic Agents; D007094:Imides; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D011956:Receptors, Cell Surface; D018110:Receptors, Lipoprotein