In vivo evidence that the lipid-regulating activity of the ACAT inhibitor CI-976 in rats is due to inhibition of both intestinal and liver ACAT.

摘要: CI-976, a new trimethoxy fatty acid anilide, is potent and specific inhibitor of liver intestinal acyl coenzyme A:cholesterol acyltransferase (ACAT) in vitro. Several vivo approaches were used to determine the efficacy sites action this compound rats. CI-976 decreased non-high density lipoprotein (HDL)-cholesterol increased HDL-cholesterol rats with pre-established dyslipidemia. High performance gel chromatographic separation plasma lipoproteins also revealed that but not CL 277,082, lowered low (LDL)-cholesterol elevated HDL-cholesterol. Bay o 2752, octimibate, melinamide, SaH 58-035 all less compared produced greatest decrease cholesteryl esters. Subcutaneous (SC) administration was efficacious cholesterol-fed animals. In sucrose-fed rats, oral SC potently triglycerides. Hepatic ester accumulation ethinyl estradiol-treated rat diminished by orally administered CI-976. ACAT activity mass dose-dependently livers from treated suggesting direct effect on liver. both hypercholesterolemic hypertriglyceridemic models, apoB concentrations. other experiments radiolabeled accumulated after multiple doses. Time-dependent changes biliary lipid bile secretion suggested free cholesterol did accumulate instead excreted as such or acid. Finally, inhibition endogenous exogenous absorption demonstrated using several techniques. The combined data strongly supports hypothesis inhibits hepatic ACAT, these enzymes may be determinants concentrations rat.