Inhibition of mPGES‐2 ameliorates NASH by activating NR1D1 via heme
Inhibition of mPGES‐2 ameliorates NASH by activating NR1D1 via heme
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DOI：
10.1002/hep.32671
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发表时间：
2022-07
期刊：
影响因子：
13.5
通讯作者：
Dandan Zhong;Jie Cai;Cheng Hu;Jingshuo Chen;Rumeng Zhang;Chenyu Fan;Shanshan Li;Hongxing Zhang;Zhou Xu;Zhanjun Jia;Dong Guo;Ying Sun
中科院分区：
文献类型：
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作者：
Dandan Zhong;Jie Cai;Cheng Hu;Jingshuo Chen;Rumeng Zhang;Chenyu Fan;Shanshan Li;Hongxing Zhang;Zhou Xu;Zhanjun Jia;Dong Guo;Ying Sun
背景和目的：非酒精性脂肪性肝病(NAFLD)是一种复杂的代谢综合征，治疗选择有限。微粒体前列腺素E合成酶-2(mPGES-2)最初被发现是一种前列腺素E_2(PGE_2)合成酶，但在肝脏中不产生PGE_2。此外，mPGES-2在NAFLD中的作用尚不清楚。本研究旨在探讨mPGES-2在肝脏脂肪变性和脂肪性肝炎中的作用及其机制。方法和结果：为了评价mPGES-2在NAFLD中的作用，采用了高脂或蛋氨酸胆碱缺乏饮食的全身或肝细胞特异性mPGES-2缺陷小鼠。与对照组相比，mPGES-2缺陷小鼠的肝脏脂质堆积减少，肝脏损伤、炎症和纤维化得到改善。此外，mPGES-2缺乏对NAFLD的保护作用依赖于细胞色素P4504A14的减少和血红素受体亚家族D成员1(NR1D1)调节的酰基辅酶A硫酯酶4水平的升高，而不是PGE2。血红素对mPGES-2缺乏所介导的NR1D1活性升高具有调节作用。进一步，我们证实了mPGES-2抑制剂SZ0232在NAFLD治疗中的保护作用。结论：我们的研究提示了mPGES-2的致病作用，并概述了其在NAFLD中的作用机制，从而突出了抑制mPGES-2在肝脏脂肪变性和脂肪性肝炎中的治疗潜力。
Background and Aims: Nonalcoholic fatty liver disease (NAFLD), a complex metabolic syndrome, has limited therapeutic options. Microsomal prostaglandin E synthase‐2 (mPGES‐2) was originally discovered as a prostaglandin E2 (PGE2) synthase; however, it does not produce PGE2 in the liver. Moreover, the role of mPGES‐2 in NAFLD remains undefined. Herein, we aimed to determine the function and mechanism of mPGES‐2 in liver steatosis and steatohepatitis. Approach and Results: To evaluate the role of mPGES‐2 in NAFLD, whole‐body or hepatocyte‐specific mPGES‐2–deficient mice fed a high‐fat or methionine‐choline‐deficient diet were used. Compared with control mice, mPGES‐2–deficient mice showed reduced hepatic lipid accumulation, along with ameliorated liver injury, inflammation, and fibrosis. Furthermore, the protective effect of mPGES‐2 deficiency against NAFLD was dependent on decreased cytochrome P450 4A14 and increased acyl‐CoA thioesterase 4 levels regulated by the heme receptor nuclear receptor subfamily 1 group D member 1 (NR1D1), but not PGE2. Heme regulated the increased NR1D1 activity mediated by mPGES‐2 deficiency. Further, we confirmed the protective role of the mPGES‐2 inhibitor SZ0232 in NAFLD therapy. Conclusion: Our study indicates the pathogenic role of mPGES‐2 and outlines the mechanism in mediating NAFLD, thereby highlighting the therapeutic potential of mPGES‐2 inhibition in liver steatosis and steatohepatitis.