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

Changle Ke; Changchen Xiao; Jiamin Li; Xianpeng Wu; Yu Zhang; Yongjian Chen; Shuyuan Sheng; Zaiyang Fu; Lingjun Wang; Cheng Ni; Jing Zhao; Yanna Shi; Yan Wu; Zhiwei Zhong; Jinliang Nan; Wei Zhu; Jinghai Chen; Rongrong Wu; Xinyang Hu

doi:10.1097/HEP.0000000000000643

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

Hepatology. 2023 Oct 24. doi: 10.1097/HEP.0000000000000643. Online ahead of print.

Authors

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}

Affiliations

¹ Department of Cardiology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, P.R.China.
² State Key Laboratory of Transvascular Implantation Devices, Hangzhou, P.R.China.
³ Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, P.R.China.
⁴ Institute of Translational Medicine, College of Medicine, Zhejiang University, Hangzhou, P.R.China.
⁵ Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, P.R.China.

PMID: 37874228
DOI: 10.1097/HEP.0000000000000643

Abstract

Background and aims: NAFLD comprises a spectrum of liver disorders with the initial abnormal accumulation of lipids in hepatocytes called NAFL, progressing to the more serious 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 patients with NAFL/NASH and mouse models. Both global and hepatocyte-specific knockout of FMO2 resulted in increased lipogenesis and severe 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 and its subsequent activation, thus suppressing de novo lipogenesis (DNL) and improving NAFL/NASH.

Conclusions: In hepatocytes, FMO2 is a novel molecule that protects against the progression of NAFL/NASH independent of enzyme activity. FMO2 impairs lipogenesis in high-fat diet-induced or choline-deficient, methionine-deficient, amino acid-defined high-fat diet-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.