| Abstract: | OBJECTIVE: Obeticholic acid (OCA), a farnesoid X receptor (FXR) agonist, is believed to alleviate nonalcoholic fatty liver disease (NAFLD) by decreasing hepatic lipogenesis in an FXR-dependent manner. Here, we revealed a novel mechanism by which OCA improves NAFLD by affecting hepatic long-chain fatty acids (LCFAs) uptake. METHODS: Stably transfected HEK-293 cells expressing fatty acid transport protein 5 (FATP5) were established to examine fatty acid uptake; FXR-/-, human (h) FATP5, and FXR-/-/hFATP5 mouse models were incorporated to explore the effects of OCA on FATP5 ex vivo and in vivo. RESULTS: OCA inhibited hFATP5 (IC50 =0.07 μM) more than murine (m) FATP5 (IC50 =1.04 μM) as measured by LCFAs uptake in FATP5 expressing HEK-293. OCA also inhibited LCFA uptake in primary hepatocytes from hFATP5 mice, FXR-/-/hFATP5 mice more than that from FXR-/- mice, ex vivo. Moreover, OCA inhibited LCFAs uptake by livers in hFATP5 mice and FXR-/-/hFATP5 mice, but not in FXR-/- mice, in vivo. Long-term administration of 0.04% OCA markedly reduced hepatic triglyceride (TG) accumulation in hFATP5 mice and FXR-/-/hFATP5 mice by 63% and 53%, respectively, but not in FXR-/- mice. CONCLUSIONS: OCA ameliorated high-fat diet-induced NAFLD independent of FXR by inhibiting hepatic hFATP5-mediated LCFAs uptake. This suggests that the therapeutic effects of OCA on NAFLD in vivo are mediated by a novel, hFATP5 dependent mechanism. |
