Inhibition of acyl-coenzyme A:cholesterol acyltransferase stimulates cholesterol efflux from macrophages and stimulates farnesoid X receptor in hepatocytes

Abstract

We investigated the mechanism of spontaneous cholesterol efflux induced by acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibition, and how an alteration of cholesterol metabolism in macrophages impacts on that in HepG2 cells. Oleic acid anilide (OAA), a known ACAT inhibitor reduced lipid storage substantially by promotion of cholesterol catabolism and repression of cholesteryl ester accumulation without further increase of cytotoxicity in acetylated low-density lipoprotein-loaded THP-1 macrophages. Analysis of expressed mRNA and protein revealed that cholesterol 7α-hydroxylase (CYP7A1), oxysterol 7α-hydroxylase (CYP7B1), and cholesterol 27-hydroxylase (CYP27) were highly induced by ACAT inhibition. The presence of a functional cytochrome P450 pathway was confirmed by quantification of the biliary cholesterol mass in cell monolayers and extracelluar medium. Notably, massively secreted biliary cholesterol from macrophages suppressed the expression of CYP7 proteins in a farnesoid X receptor (FXR)-dependent manner in HepG2 cells. The findings reported here provide new insight into mechanisms of spontaneous cholesterol efflux, and suggest that ACAT inhibition may stimulate cholesterol-catabolic (cytochrome P450) pathway in lesion-macrophages, in contrast, suppress it in hepatocyte via FXR induced by biliary cholesterol (BC).

High-Density Lipoprotein and Coronary Heart Disease

“…Theoretically ACAT, specifically ACAT-1, inhibition would slow the progression of foam macrophage cells in theory (249). Subsequently, free cholesterol would be available for reverse cholesterol transport (250). ACAT-2, the other identified ACAT isoform, is present in the liver and intestine, so inhibition of this enzyme would reduce LDL formation (251).…”

ATR‐101 inhibits cholesterol efflux and cortisol secretion by ATP‐binding cassette transporters, causing cytotoxic cholesterol accumulation in adrenocortical carcinoma cells

“…Most ACAT inhibitors do not cause cholesterol accumulation or cytotoxicity under normal cell culture conditions, and differences in the ACAT inhibitory activities of different compounds do not correlate with differences in cytotoxicity (Junquero et al, 2001;Rodriguez and Usher, 2002;An et al, 2008;Pokhrel et al, 2012). Only a small proportion of ACAT inhibitors have adrenalytic activity, even though many of them reduce serum cholesterol levels in animals (see Sliskovic et al, 2002).…”

Honokiol, magnolol, and a combination of both compounds improve glucose metabolism in high-fat diet-induced obese mice

“…It was also reported that honokiol and magnolol inhibited ACAT, which catalyzes formation of cholesteryl esters from cholesterol and long-chain fatty acyl-CoA (12). This process represses accumulation of total cholesterol by inhibition of very lowdensity lipoprotein production in the liver and facilitation of cholesterol efflux from macrophages (20). Therefore, the mechanism by which honokiol and magnolol improve adipose and lipid disorders could be attributed, at least for regulation of genes involved in lipid metabolism, to activation of nuclear receptors as ligands and to inhibition of ACAT activity.…”