Hydroxyeicosapentaenoic acids and epoxyeicosatetraenoic acids attenuate early occurrence of nonalcoholic fatty liver disease

作者：Wang, Chunjiong; Liu, Wenli; Yao, Liu; Zhang, Xuejiao; Zhang, Xu; Ye, Chenji; Jiang, Hongfeng; He, Jinlong; Zhu, Yi; Ai, Ding^*

来源：British Journal of Pharmacology, 2017, 174(14): 2358-2372.

DOI：10.1111/bph.13844

• INDUCED OBESE MICE
• INSULIN-RESISTANCE
• ADIPOSE-TISSUE
• EICOSAPENTAENOIC ACID
• HEPATIC STEATOSIS
• CONCISE GUIDE
• DOCOSAHEXAENOIC ACID
• INFLAMMATION
• DIET
• TERM

BACKGROUND AND PURPOSE @@@ The omega-3 polyunsaturated fatty acids (PUFAs) mediate protective effects on several metabolic disorders. However, the functions of their metabolites in the early stage of nonalcoholic fatty liver disease (NAFLD) are largely unknown. @@@ EXPERIMENTAL APPROACH @@@ Mice were fed a control diet, high-fat diet (HFD) or omega-3 PUFA-enriched HFD (omega 3HFD) for 4 days and phenotypes were analysed. LC-MS/MS was used to determine the eicosanoid profiles. Primary hepatocytes and peritoneal macrophages were used for the mechanism study. @@@ KEY RESULTS @@@ In short-term HFD-fedmice, the significantly increased lipid accumulation in the liver was reversed by omega-3 PUFA supplementation. Metabolomics showed that the plasma concentrations of hydroxyeicosapentaenoic acids (HEPEs) and epoxyeicosatetraenoic acids (EEQs) were reduced by a short-term HFD and markedly increased by the omega 3HFD. However, HEPE/EEQ treatment had no direct protective effect on hepatocytes. omega 3HFD also significantly attenuated HFD-induced adipose tissue inflammation. Furthermore, the expression of pro-inflammatory cytokines and activation of the JNK pathway induced by palmitate were suppressed by HEPEs and EEQs in macrophages. 17,18-EEQ, 5-HEPE and 9-HEPE were identified as the effective components among these metabolites, as indicated by their greater suppression of the palmitate-induced expression of inflammatory factors, chemotaxis and JNK activation compared to other metabolites in macrophages. A mixture of 17,18-EEQ, 5-HEPE and 9-HEPE significantly ameliorated the short-term HFD-induced accumulation of macrophages in adipose tissue and hepatic steatosis. @@@ CONCLUSION AND IMPLICATIONS @@@ 17,18-EEQ, 5-HEPE and 9-HEPE may be potential approaches to prevent NAFLD in the early stage by inhibiting the inflammatory response in adipose tissue macrophages via JNK signalling.

• 出版日期2017-7
• 单位天津医科大学