Effect of the ACAT inhibitor CL 277,082 on apolipoprotein B48 transport in mesenteric lymph and on plasma clearance of chylomicrons and remnants.

Abstract

Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) activity previously have been found to decrease the absorption of cholesterol and to be effective antiatherosclerotic agents. Effects on chylomicron (CM) transport could contribute to these effects. No previous study has examined the effect of inhibition of ACAT activity on the intestinal lymph output of apolipoprotein (apo) B48 or on the clearance from plasma of lymph CM. In this study, we selected 2,4-difluoro-phenyl-N[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-( hepthyl)urea (CL 277,082) to inhibit intestinal ACAT activity and measured its effects on the output of lipids and apo B48 in intestinal lymph. Compared with control untreated rats, treatment with CL 277,082 decreased the lymph outputs of apo B48 and triglyceride. Associated with the effects on transport, the lymph CM were smaller in diameter in rats treated with CL 277,082. The unesterified cholesterol content of lymph CM was markedly increased and the cholesteryl ester (CE) content was decreased. The contents of triglyceride were decreased and phospholipid was increased. Labeled CM were prepared by feeding donor rats with a test meal containing 3H-cholesterol and 14C-fatty acid. Traced by the CE label in lymph CM in both control rats and rats treated with CL 277,082, the remnants derived after intravenous injection of CM from rats treated with CL 277,082 were cleared significantly more slowly than CM from untreated rats. Moreover, less CE label was recovered in the livers of both groups of rats after injection of CM from rats treated with CL 277,082. Recovery in the spleen was significantly higher in recipient rats injected with CM from rats treated with CL 277,082 when compared with injections of CM obtained from untreated rats. We conclude that the metabolism of CM is affected by treatment with CL 277,082, partly due to the changes in lymph CM composition and partly due to other effects on the recipient rat.