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n-3多不饱和脂肪酸通过增加肝脏脂氧素A₅含量改善高同型半胱氨酸血症引起的肝脏脂肪变性

宋浩, 段进杰, 李侃, 姚柳^*, 朱毅

天津医科大学生理学与病理生理学系，天津 300070

摘要

非酒精性脂肪性肝脏疾病与高同型半胱氨酸血症(hyperhomocysteinemia, HHcy)均为世界范围内的重要健康问题，二者发病密切相关。我们前期报道了HHcy引起脂肪肝的作用机制，但n-3多不饱和脂肪酸(n-3 polyunsaturated fatty acid, n-3 PUFA)在其中的作用尚未有明确报道。本研究通过给予6周龄C57BL/6雄性小鼠高蛋氨酸饮食(2% high methionine diet, HMD)，通过ELISA技术检测血浆同型半胱氨酸的水平，以明确HHcy模型的建立。同时添加或不添加n-3 PUFA喂养，以明确n-3 PUFA在HHcy引起肝脏脂肪变性中的作用及机制。结果显示，n-3 PUFA显著改善了HHcy引起的肝脏脂质沉积。qRT-PCR分析发现n-3 PUFA抑制了HHcy诱导的脂肪酸摄取关键基因Cd36的表达。进一步分析发现Cd36的表达降低与n-3 PUFA引起的芳香烃受体(aryl hydrocarbon receptor, Ahr)活性抑制相关。利用PUFA靶向代谢组学分析发现，与HMD组相比，n-3 PUFA明显增加了肝脏二十碳五烯酸代谢产物脂氧素A5 (lipoxin A5, LXA5)的含量。用LXA5处理分离的原代肝细胞，阻断了同型半胱氨酸诱导的Cd36表达上调和Ahr激活，减轻了脂质沉积。以上结果表明，n-3 PUFA通过增加肝脏LXA5的含量，抑制HHcy引起的Ahr-Cd36信号通路的激活，改善肝脏的脂肪变性。本研究结果预期可为非酒精性脂肪性肝脏疾病的临床治疗开辟新的途径。

关键词： 高同型半胱氨酸血症; 肝脏脂肪变性; 氧素A5; 芳香烃受体; Cd36

分类号：R33

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

收稿日期：2021-01-23　　录用日期：2021-04-08

通讯作者：姚柳　　E-mail: yaoliu@tmu.edu.cn

DOI: 10.13294/j.aps.2021.0057

引用本文：

宋浩, 段进杰, 李侃, 姚柳, 朱毅. n-3多不饱和脂肪酸通过增加肝脏脂氧素A₅含量改善高同型半胱氨酸血症引起的肝脏脂肪变性[J]. 生理学报 2021; 73 (4): 551-558.

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).