Fenofibrate and LXR alpha agonist combination attenuated intrahepatic inflammation in non-alcoholic fatty liver

Abstract

Background/Aims: Liver X receptors (LXR) is key transcription factor in the regulation of lipid and cholesterol metabolism, in addition, LXRα has been implicated as regulator of inflammation. LXRα activation is associated with hepatic steatosis and hyperlipidemia in mice. Fenofibrate, a PPARα agonist and omega-3, an antihypertriglyceride agent, lead to a reduction of hyperlipidemia. The aim of this study to investigate whether concurrent effect of LXRα and fenofibrate or omega-3 can produce synergic benefits in high-fat diet induced obese mice. Methods: Normal chow and high-fat diet mice treated with LXRα agonist (T0901317), or combined fenofibrate or omega-3 for 4 weeks. Hematoxylin and eosin staining was performed on liver tissue extracts after animal sacrifice. SREBP1c, FAS, SCD-1, PPAR-α, and MCP-1 mRNA expressions were assessed with reverse transcription-polymerase chain reaction. Results: LXRα agonist increase intrahepatic fat amount in normal chow group. Degree of intrahepatic inflammation was not different among LXRα agonist, or combined with fenofibrate/omega-3. In NAFLD model, the combined treatment with fenofibrate did not increase hepatic steatosis. LXRα agonist and/or fenofibrate or omega-3 decreased intrahepatic inflammation. In high-fat diet groups, combined treatment with fenofibrate markedly reduced the expression of genes involved in lipogenesis, including srebp-1c, fas and scd1. Furthermore, LXRα agonist and/or fenofibrate or omega3 treatment decreased expression of abca-1, abcg5, and abcg8 genes, three vital genes for cholesterol efflux in diet induced fatty liver model, but those expressions were opposite in normal chow group. Intraheptic MCP-1, and TNF-α expression and markers of inflammasome were also decreased in NAFLD group. Conclusion: LXRα agonist and fenofibrate combination treatment attenuated hepatic inflammation in NAFLD model. Disclosures: The following authors have nothing to disclose: Eun Chul Jang, Dae Won Jun, Seung Min Lee, Yong Kyun Cho, Sang Bong Ahn