Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat

Jul 27, 1999Hepatology (Baltimore, Md.)

Avasimibe increases bile acid production and cholesterol-processing enzyme in rat liver cells and live rats

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Abstract

Avasimibe reduced plasma cholesterol levels by 52% to 71% in rats fed various diets.

Avasimibe decreased ACAT activity in rat liver cells by 93% and 75% at doses of 10 micromol/L.
Treatment with avasimibe increased bile acid synthesis by 2.9-fold and cholesterol 7alpha-hydroxylase activity by 1.7- and 2.6-fold.
The drug promoted a shift in liver cells from storing cholesteryl esters to converting cholesterol into bile acids.
In cholesterol-fed rats, avasimibe prevented the down-regulation of cholesterol 7alpha-hydroxylase activity by cholate.
ACAT inhibition by avasimibe did not lead to a more lithogenic bile, as indicated by no increase in the ratio of biliary cholesterol to bile acids.

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Acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors are currently in clinical development as potential lipid-lowering and antiatherosclerotic agents. We investigated the effect of avasimibe (Cl- 1011), a novel ACAT inhibitor, on bile acid synthesis and cholesterol 7alpha-hydroxylase in cultured rat hepatocytes and rats fed different diets. Avasimibe dose-dependently decreased ACAT activity in rat hepatocytes in the presence and absence of beta-migrating very low-density lipoproteins (betaVLDL) (by 93% and 75% at 10 micromol/L) and reduced intracellular storage of cholesteryl esters. Avasimibe (3 micromol/L) increased bile acid synthesis (2.9-fold) after preincubation with betaVLDL and cholesterol 7alpha-hydroxylase activity (1.7- and 2.6-fold, with or without betaVLDL), the latter paralleled by a similar induction of its messenger RNA (mRNA). Hepatocytes treated with avasimibe showed a shift from storage and secretion of cholesteryl esters to conversion of cholesterol into bile acids. In rats fed diets containing different amounts of cholesterol and cholate, avasimibe reduced plasma cholesterol (by 52% to 71%) and triglyceride levels (by 28% to 62%). Avasimibe did not further increase cholesterol 7alpha-hydroxylase activity and mRNA in cholesterol-fed rats, but prevented down-regulation by cholate. Avasimibe did not affect sterol 27-hydroxylase and oxysterol 7alpha-hydroxylase, 2 enzymes in the alternative pathway in bile acid synthesis. No increase in the ratio of biliary excreted cholesterol to bile acids was found, indicating that ACAT inhibition does not result in a more lithogenic bile. Avasimibe increases bile acid synthesis in cultured hepatocytes by enhancing the supply of free cholesterol both as substrate and inducer of cholesterol 7alpha-hydroxylase. These effects may partially explain the potent cholesterol-lowering effects of avasimibe in the rat.

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Acyl-coenzyme A: Cholesterol acyltransferase inhibitor, avasimibe, stimulates bile acid synthesis and cholesterol 7α-hydroxylase in cultured rat hepatocytes and in vivo in the rat

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