FMO2 ameliorates nonalcoholic fatty liver disease by suppressing ER-to-Golgi transport of SREBP1.,Hepatology

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FMO2 ameliorates nonalcoholic fatty liver disease by suppressing ER-to-Golgi transport of SREBP1.
Hepatology ( IF 13.5 ) Pub Date : 2023-10-24 , DOI: 10.1097/hep.0000000000000643
Changle Ke _{1,

2,

3} , Changchen Xiao _{1,

2,

3} , Jiamin Li _{1,

2,

3} , Xianpeng Wu _{1,

2,

3} , Yu Zhang _{1,

2,

3} , Yongjian Chen _{1,

2,

3} , Shuyuan Sheng _{1,

2,

3} , Zaiyang Fu _{1,

2,

3} , Lingjun Wang _{1,

2,

3} , Cheng Ni _{1,

2,

3} , Jing Zhao _{1,

2,

3} , Yanna Shi _{1,

2,

3} , Yan Wu _{1,

2,

3} , Zhiwei Zhong _{1,

2,

3} , Jinliang Nan _{1,

2,

3} , Wei Zhu _{1,

2,

3} , Jinghai Chen _{1,

3,

4} , Rongrong Wu _{1,

2,

3} , Xinyang Hu _{1,

2,

3,

5}

Affiliation

BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD), comprises a spectrum of liver disorders with the initial abnormal accumulation of lipids in hepatocytes called nonalcoholic fatty liver (NAFL), progressing to the more serious non-alcoholic steatohepatitis (NASH) in a subset of individuals. Our previous study revealed that global flavin-containing monooxygenase 2 (FMO2) knockout causes higher liver weight in rats. However, the role of FMO2 in NAFLD remains unclear. Herein, we aimed to determine the function and mechanism of FMO2 in liver steatosis and steatohepatitis. APPROACH AND RESULTS The expression of FMO2 was significantly downregulated in NAFL/NASH patients and mouse model. Both global and hepatocyte-specific knockout of FMO2 resulted in increased lipogenesis and severer hepatic steatosis, inflammation, and fibrosis, whereas FMO2 overexpression in mice improved NAFL/NASH. RNA sequencing showed that hepatic FMO2 deficiency is associated with impaired lipogenesis in response to metabolic challenges. Mechanistically, FMO2 directly interacts with SREBP1 at amino acids 217-296 competitively with SREBP cleavage-activating protein (SCAP) and inhibits SREBP1 translocation from the endoplasmic reticulum (ER) to the Golgi apparatus (GA) and its subsequent activation, thus suppressing de novo lipogenesis (DNL) and improving NAFL/NASH. CONCLUSION In hepatocytes, FMO2 is a novel molecule that protects against the progression of NAFL/NASH independent of enzyme activity. FMO2 impairs lipogenesis in HFD or CDAHFD-induced steatosis, inflammation and fibrosis by directly binding to SREBP1 and preventing its organelle translocation and subsequent activation. FMO2 thus is a promising molecule for targeting the activation of SREBP1 and for the treatment of NAFL/NASH.

中文翻译：

FMO2 通过抑制 SREBP1 的 ER 至高尔基体转运来改善非酒精性脂肪肝。

背景和目的非酒精性脂肪肝病 (NAFLD) 包括一系列肝脏疾病，最初是肝细胞中脂质异常积累，称为非酒精性脂肪肝 (NAFL)，在部分人群中进展为更严重的非酒精性脂肪性肝炎 (NASH)个人。我们之前的研究表明，整体含黄素单加氧酶 2 (FMO2) 敲除会导致大鼠肝脏重量增加。然而，FMO2 在 NAFLD 中的作用仍不清楚。在此，我们的目的是确定FMO2在肝脏脂肪变性和脂肪性肝炎中的功能和机制。方法和结果 FMO2 的表达在 NAFL/NASH 患者和小鼠模型中显着下调。FMO2 的整体敲除和肝细胞特异性敲除都会导致脂肪生成增加和更严重的肝脏脂肪变性、炎症和纤维化，而小鼠体内 FMO2 过表达则改善 NAFL/NASH。RNA 测序表明，肝脏 FMO2 缺乏与应对代谢挑战的脂肪生成受损有关。从机制上讲，FMO2 与 SREBP1 的氨基酸 217-296 直接与 SREBP 裂解激活蛋白 (SCAP) 竞争性相互作用，并抑制 SREBP1 从内质网 (ER) 易位到高尔基体 (GA) 及其随后的激活，从而抑制从头开始脂肪生成 (DNL) 和改善 NAFL/NASH。结论在肝细胞中，FMO2 是一种新型分子，可防止 NAFL/NASH 进展，且与酶活性无关。FMO2 通过直接与 SREBP1 结合并阻止其细胞器易位和随后的激活，从而损害 HFD 或 CDAHFD 诱导的脂肪变性、炎症和纤维化中的脂肪生成。因此，FMO2 是一种有前景的分子，可用于靶向激活 SREBP1 并用于治疗 NAFL/NASH。

更新日期：2023-10-24

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