An ACAT-1Inhibitor, K-604, Ameliorates Hepatic Inflammation in NAFLD and NASH Models

Abstract

A high level of cholesterol activates Kupffer cells, which subsequently triggers inflammation and ultimately leads to steatohepatitis. The number of Kupffer cells correlates with the inflammatory grade of Non-Alcoholic Fatty Liver Disease (NAFLD). In this study, we studied the role of 'foamy' Kupffer cells in the nexus between inflammation and steatosis and investigated whether K-604, a selective Acyl-Coenzyme A: Cholesterol Acyltransferase-1 (ACAT-1) inhibitor ameliorates hepatic steatosis and inflammation in rodent models of NAFLD and Non-Alcoholic Steatohepatitis (NASH). Methionine-and Choline-Deficient (MCD) diet-fed KK-Ay mice, High-Fat and High-Cholesterol (HFC) diet-fed Low-Density Lipoprotein Receptor-Deficient (Ldlr(−/−)) mice and Zucker fatty rats were evaluated after 16, 16 and 12 weeks of K-604 treatment. The biochemical parameters, hepatic lipid levels, histopathological changes and gene expression levels were assessed. In the MCD diet-fed KK-Ay mice, K-604 significantly improved the NASH symptoms. In the HFC diet-fed Ldlr (−/−) mice, K-604 suppressed the inflammatory gene expression and reduced the number of inflammatory foci. Moreover, K-604 decreased the area and size of foamy Kupffer cells. In the Zucker fatty rats, K-604 could also inhibit hepatic steatosis. These results indicated that K-604 acts directly on Kupffer cells and inhibits hepatic inflammation, suggesting that ACAT-1 is involved in the progression of steatohepatitis. Therefore, ACAT-1 inhibition may be a new therapeutic target for NAFLD and NASH.