n-3 fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice

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 4weeks 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.

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.