Enzymatically-epoxidized docosahexaenoic acid, 19,20-EpDPE, suppresses hepatic crown-like structure formation and nonalcoholic steatohepatitis fibrosis through GPR120
Enzymatically-epoxidized docosahexaenoic acid, 19,20-EpDPE, suppresses hepatic crown-like structure formation and nonalcoholic steatohepatitis fibrosis through GPR120
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DOI：
10.1016/j.bbalip.2022.159275
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发表时间：
2023-01-04
影响因子：
4.8
通讯作者：
Arita, Makoto
中科院分区：
文献类型：
--
作者：
Aoki, Hidenori;Isobe, Yosuke;Arita, Makoto
由巨噬细胞聚集在肝脏中的脂滴和死细胞周围形成的肝冠状结构（hCLS）是非酒精性脂肪性肝炎（NASH）的独特特征，其触发肝纤维化的进展。由于hCLS在NASH纤维化的进展中起关键作用，hCLS形成已成为潜在的治疗靶点。n-3多不饱和脂肪酸（n-3 PUFA）对NASH纤维化具有潜在的抑制作用;然而，这种作用的机制尚不清楚。在这里，我们报告了富含n-3 PUFA的Fat-1转基因小鼠在高脂饮食、CCl 4和肝脏X受体（LXR）激动剂联合诱导的NASH模型中对hCLS形成和肝纤维化具有抗性。基于液相色谱-串联质谱法的介质脂质组学显示，内源性n-3 PUFA衍生的代谢物，如17，18-二羟基二十碳四烯酸（17，18-diHETE）和19，20-环氧二十二碳五烯酸（19，20-EpDPE）的量在Fat-1小鼠中显著升高，沿着hCLS形成。特别是，由Cyp 4f 18产生的DHA衍生的19，20-EpDPE以G蛋白偶联受体120（GPR 120）依赖性方式减弱hCLS形成和肝纤维化。这些结果表明，19，20-EpDPE是介导n-3 PUFA对NASH纤维化的预防作用的内源性活性代谢物。
A hepatic crown-like structure (hCLS) formed by macrophages accumulating around lipid droplets and dead cells in the liver is a unique feature of nonalcoholic steatohepatitis (NASH) that triggers progression of liver fibrosis. As hCLS plays a key role in the progression of NASH fibrosis, hCLS formation has emerged as a potential ther-apeutic target. n-3 polyunsaturated fatty acids (n-3 PUFAs) have potential suppressive effects on NASH fibrosis; however, the mechanisms underlying this effect are poorly understood. Here, we report that n-3 PUFA-enriched Fat-1 transgenic mice are resistant to hCLS formation and liver fibrosis in a NASH model induced by a combi-nation of high-fat diet, CCl4 and a Liver X receptor (LXR) agonist. Liquid chromatography-tandem mass spectrometry-based mediator lipidomics revealed that the amount of endogenous n-3 PUFA-derived metabolites, such as 17,18-dihydroxyeicosatetraenoic acid (17,18-diHETE), and 19,20-epoxy docosapentaenoic acid (19,20-EpDPE), was significantly elevated in Fat-1 mice, along with hCLS formation. In particular, DHA-derived 19,20-EpDPE produced by Cyp4f18 attenuated the hCLS formation and liver fibrosis in a G protein-coupled receptor 120 (GPR120)-dependent manner. These results indicated that 19,20-EpDPE is an endogenous active metabolite that mediates the preventive effect of n-3 PUFAs against NASH fibrosis.