N−3 Fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice

Abstract

Liver X receptor (LXR) agonists slow atherogenesis, but cause hepatic steatosis and dysfunction in part by increasing expression of sterol regulatory element binding protein 1-c (SREBP1-c), a transcription factor that upregulates fatty acid (FA) synthesis. n−3 FAs decrease hepatic FA synthesis by down-regulating SREBP1-c. To test the hypothesis that n−3 FAs decrease hepatic steatosis in mice given LXR agonist, C57BL/6 mice received daily gavage of an LXR agonist T0901317 (LXR T) or vehicle for 4 weeks with concomitant intakes chow or high-fat diets enriched in saturated fat (SAT) or n−3 fat (n−3). Mice on LXR T and SAT developed hepatomegaly with a large increase in size and number of hepatic lipid droplets; an n−3 diet reduced liver weight/body weight with decreased hepatic steatosis and triglyceride levels. Effects of n−3 diet on hepatic lipogenesis were linked to a blunting of LXR T upregulation of hepatic SREBP1-c and FA synthase mRNA. n−3 diets also normalized LXR T-mediated increases of plasma ALT and AST levels, whereas SAT diet increased these markers. Conclusion: These studies suggest that n−3 FAs when given together with LXR agonists have the potential to improve both hepatic steatosis and hepatotoxicity in humans that might receive LXR agonists to decrease risk of atherosclerosis.