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n-3 Polyunsaturated fatty acid attenuates hyperhomocysteinemia-induced hepatic steatosis by increasing hepatic LXA₅ content

SONG Hao, DUAN Jin-Jie, LI Kan, YAO Liu^*, ZHU Yi

Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin 300070, China

Abstract

Nonalcoholic fatty liver disease (NAFLD) and hyperhomocysteinemia (HHcy) both are major health problems worldwide, whose incidence are closely related with each other. We previously reported the mechanism of HHcy-caused hepatic steatosis, but the role of n-3 polyunsaturated fatty acid (n-3 PUFA) in HHcy-induced hepatic steatosis remains unclear. In this study, 6-week-old C57BL/6 male mice were given a high methionine diet (HMD, 2% methionine diet), and plasma homocysteine levels were measured by ELISA to confirm the establishment of an HHcy model. Meantime, mice were fed HMD with or without n-3 PUFA supplement for 8 weeks to determine the role and mechanism of n-3 PUFA in hepatic steatosis induced by HHcy. Results showed that n-3 PUFA significantly improved hepatic lipid deposition induced by HHcy. qRT-PCR analysis demonstrated that n-3 PUFA inhibited the upregulation of Cd36, a key enzyme of fatty acid uptake, caused by HHcy. Further, the inhibition of hepatic Cd36 expression was associated with the inactivation of aryl hydrocarbon receptor (Ahr) induced by n-3 PUFA. Of note, mass spectrometry revealed that hepatic content of lipoxin A5 (LXA5) was significantly increased in HMD+n-3 PUFA-fed mice compared with that in HMD-fed mice. In primary cultured hepatocytes, LXA5 treatment markedly reversed homocysteine-evoked Cd36 upregulation and Ahr activation, which resulted in reduced lipid accumulation. In conclusion, we demonstrate that n-3 PUFA inactivates HHcy-induced Ahr-Cd36 pathway by increasing hepatic LXA5 content, which alleviates hepatic steatosis. Thus, our results may provide a potential strategy for treatment of NAFLD.

Key words: hyperhomocysteinemia; hepatic steatosis; lipoxin A5; aryl hydrocarbon receptor; Cd36

Received: 2021-01-23　　Accepted: 2021-04-08

Corresponding author: 姚柳　　E-mail: yaoliu@tmu.edu.cn

DOI: 10.13294/j.aps.2021.0057

Citing This Article：

SONG Hao, DUAN Jin-Jie, LI Kan, YAO Liu, ZHU Yi. n-3 Polyunsaturated fatty acid attenuates hyperhomocysteinemia-induced hepatic steatosis by increasing hepatic LXA₅ content. Acta Physiol Sin 2021; 73 (4): 551-558 (in Chinese with English abstract).