Periostin Protects Against Alcohol-related Liver Disease by Activating Autophagy by Interacting With Protein Disulfide Isomerase

Yanfei Zhang; Jiayu Jin; Heming Wu; Jingwen Huang; Shuting Ye; Jinhua Qiu; Gaoliang Ouyang; Tiantian Wu; Fan Liu; Yingfu Liu

doi:10.1016/j.jcmgh.2023.02.005

Periostin Protects Against Alcohol-related Liver Disease by Activating Autophagy by Interacting With Protein Disulfide Isomerase

Cell Mol Gastroenterol Hepatol. 2023;15(6):1475-1504. doi: 10.1016/j.jcmgh.2023.02.005. Epub 2023 Feb 18.

Authors

Yanfei Zhang¹, Jiayu Jin¹, Heming Wu², Jingwen Huang¹, Shuting Ye¹, Jinhua Qiu², Gaoliang Ouyang¹, Tiantian Wu³, Fan Liu⁴, Yingfu Liu⁵

Affiliations

¹ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China.
² Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China.
³ State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen, China. Electronic address: wutiantian@xmu.edu.cn.
⁴ Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China. Electronic address: liufan@xmu.edu.cn.
⁵ Department of Basic Medical Sciences, School of Medicine, Xiamen University, Xiamen, China. Electronic address: liuyingfu@xmu.edu.cn.

Abstract

Background & aims: The matricellular protein periostin plays a critical role in liver inflammation, fibrosis, and even carcinoma. Here, the biological function of periostin in alcohol-related liver disease (ALD) was investigated.

Methods: We used wild-type (WT), Postn-null (Postn^-/-) mice and Postn^-/- mice with periostin recovery to investigate the biological function of periostin in ALD. Proximity-dependent biotin identification analysis identified the protein that interacted with periostin, and coimmunoprecipitation analysis validated the interaction between protein disulfide isomerase (PDI) and periostin. Pharmacological intervention and genetic knockdown of PDI were used to investigate the functional correlation between periostin and PDI in ALD development.

Results: Periostin was markedly upregulated in the livers of mice that were fed ethanol. Interestingly, periostin deficiency severely aggravated ALD in mice, whereas the recovery of periostin in the livers of Postn^-/- mice significantly ameliorated ALD. Mechanistic studies showed that the upregulation of periostin alleviated ALD by activating autophagy through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which was verified in murine models treated with the mTOR inhibitor rapamycin and the autophagy inhibitor MHY1485. Furthermore, a protein interaction map of periostin was generated by proximity-dependent biotin identification analysis. Interaction profile analysis identified PDI as a key protein that interacted with periostin. Intriguingly, periostin-mediated enhancement of autophagy by inhibiting the mTORC1 pathway in ALD depended on its interaction with PDI. Moreover, alcohol-induced periostin overexpression was regulated by transcription factor EB.

Conclusions: Collectively, these findings clarify a novel biological function and mechanism of periostin in ALD and the periostin-PDI-mTORC1 axis is a critical determinant of ALD.

Keywords: ALD; BioID; Hepatic Steatosis; PDI; Periostin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Autophagy
Biotin / metabolism
Ethanol / toxicity
Hepatocytes* / metabolism
Liver Diseases, Alcoholic* / pathology
Mechanistic Target of Rapamycin Complex 1 / metabolism
Mice
Protein Disulfide-Isomerases / genetics
Protein Disulfide-Isomerases / metabolism

Substances

Protein Disulfide-Isomerases
Biotin
Ethanol
Mechanistic Target of Rapamycin Complex 1