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

doi:10.1016/j.biopha.2022.112984

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

Biomed Pharmacother. 2022 Jun:150:112984. doi: 10.1016/j.biopha.2022.112984. Epub 2022 Apr 18.

Authors

Affiliations

¹ Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510630, China.
² Department of Gastrointestinal Endoscopy of Dongpu Branch, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510660, China.
³ Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China.
⁴ Department of Gastroenterology, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, Guangdong 510630, China. Electronic address: biaonie@jnu.edu.cn.

PMID: 35447541
DOI: 10.1016/j.biopha.2022.112984

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.

Keywords: Farnesoid X receptor; Fatty acid transport protein 5; Long-chain fatty acids; Nonalcoholic fatty liver disease; Obeticholic acid.

MeSH terms

Animals
Chenodeoxycholic Acid / analogs & derivatives
Fatty Acids / metabolism
HEK293 Cells
Humans
Liver
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease* / drug therapy
Non-alcoholic Fatty Liver Disease* / metabolism

Substances

Fatty Acids
obeticholic acid
Chenodeoxycholic Acid