Obeticholic acid inhibits hepatic fatty acid uptake independent of FXR in mouse

作者：Lin, Chuangzhen; Yu, Bingqing; Liu, Xuelian; Chen, Lixin; Zhang, Zhaohui; Ye, Weixiang; Zhong, Hui; Bai, Wenke; Yang, Yuping; Nie, Biao^*

来源：Biomedicine and Pharmacotherapy, 2022, 150: 112984.

DOI：10.1016/j.biopha.2022.112984

• Nonalcoholic fatty liver disease
• Obeticholic acid
• Farnesoid X receptor
• Fatty acid transport protein 5
• Long-chain fatty acids

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 mu M) more than murine (m) FATP5 (IC50 =1.04 mu M) 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 hFATP5mediated LCFAs uptake. This suggests that the therapeutic effects of OCA on NAFLD in vivo are mediated by a novel, hFATP5 dependent mechanism.

• 单位
  南方医科大学