Obeticholic acid inhibits hepatic fatty acid uptake independent of FXR in mouse
Chuangzhen Lin, Bingqing Yu, Xuelian Liu, Lixin Chen, Zhaohui Zhang, Weixiang Ye, Hui Zhong, Wenke Bai, Yuping Yang, Biao Nie
Abstract
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. 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. 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. 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.