Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on the Cholesterol Esterification and Its Hypocholesterolemic Properties

Abstract

We investigated the effects of SMP-500, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on ACAT activities in the liver and intestine, and in macrophages. We measured its effects on the serum cholesterol levels and hepatic cholesterol content in mice, rabbits and hamsters. SMP-500 inhibited ACAT activities in rabbit liver and small intestine microsomes with IC₅₀ values of 72 and 84 nmol/l, respectively, and acted as a competitive inhibitor of rabbit liver ACAT. SMP-500 potently inhibited cholesterol esterification in rat peritoneal macrophages (IC₅₀ = 15 nmol/l). In high-fat and high-cholesterol diet-fed mice and in high-cholesterol diet-fed rabbits, SMP-500 reduced the serum cholesterol levels and the hepatic cholesterol content. SMP-500 also reduced the serum and hepatic cholesterol in normal chow-fed hamsters in a dose-dependent manner. In all the animal models, SMP-500 reduced the hepatic free cholesterol content as well as the total and esterified cholesterol. Administered orally, SMP-500 had a direct inhibitory effect on hepatic ACAT activity. These results indicate that SMP-500 is a potent and competitive ACAT inhibitor and may have a therapeutic potential for treating hypercholesterolemia and atherosclerosis.

Effect of SMP-500, a Novel Acyl-CoA:Cholesterol Acyltransferase Inhibitor, on Serum Cholesterol Level and LDL Cholesterol Clearance in Hamsters with Induced Hyperlipidemia

“…We recently reported that SMP-500 reduced the hepatic free cholesterol content in some animal models, i.e. hypercholesterolemic mice and rabbits, and normolipidemic hamsters [22]. These results suggest the possibility that SMP-500 increases the LDL clearance in those animals as well as in hyperlipidemic hamsters.…”

“…In addition, SMP-500 increased the LDL clearance. Recently, we reported a potent cholesterol-lowering effect of SMP-500: both effects are probably due to the suppression of cholesterol absorption in the intestine and the inhibition of VLDL release in the liver [22]. These results strongly suggest that the cholesterol-lowering effect of SMP-500 is not only due to the inhibition of ACAT activity, which leads to suppression of the cholesterol absorption in the intestine and of the VLDL release in the liver, but also to an increase in LDL clearance from the blood, as seen with HMG-CoA reductase inhibitors and anion exchange resins.…”

“…We previously reported a novel ACAT inhibitor, SMP-500, that potently inhibits ACAT and lowers cholesterol in some animals [22]. In this article, we describe the cholesterol-lowering effect of SMP-500 and its mechanism in hamsters with a diet-induced, preestablished hyperlipidemic condition.…”

Effect of SMP‐500, a novel ACAT inhibitor, on hepatic cholesterol disposition in rats

“…**P < 0.01, significantly different from HC-cont using Dunnett's multiple comparisons test; ##P < 0.01, significantly different from N-cont using Student's t-test. mice, rabbits, and hamsters (20). Interestingly, SMP-500 reduced hepatic free cholesterol contents.…”

“…Recently, we reported a novel ACAT inhibitor, SMP-500, that can potently inhibit ACAT and cause cholesterol lowering in hyperlipidemic and normolipidemic animals (20). Interestingly, SMP-500 reduced hepatic free cholesterol contents.…”