Theranostics 2019; 9(25):7566-7582. doi:10.7150/thno.36942 This issue

Research Paper

The hepatocyte-specifically expressed lnc-HSER alleviates hepatic fibrosis by inhibiting hepatocyte apoptosis and epithelial-mesenchymal transition

Kun Zhang1#, Mengxia Zhang1#, Qingbin Yao1#, Xiaohui Han1#, Yanmian Zhao1, Lina Zheng1, Guantong Li2, Qi Liu1, Yanan Chang3, Peijun Zhang4, Hongmei Cui1, Zhemin Shi1, Ting Chen1, Zhi Yao5, Tao Han2, Wei Hong1✉

1. Department of Histology and Embryology, Key Laboratory of Immune Microenvironment and Disease of Ministry of Education, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
2. The Third Central Clinical College of Tianjin Medical University, Department of Hepatology and Gastroenterology, Tianjin Third Central Hospital, Tianjin Key Laboratory of Artificial Cells, Artificial Cell Engineering Technology Research Center of Public Health Ministry, Tianjin, China
3. Department of Pathology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
4. Tianjin Central Hospital of Gynecology Obstetrics, Tianjin, China
5. Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of Ministry of Education, Tianjin Key Laboratory of Cellular and Molecular Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China
#These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Zhang K, Zhang M, Yao Q, Han X, Zhao Y, Zheng L, Li G, Liu Q, Chang Y, Zhang P, Cui H, Shi Z, Chen T, Yao Z, Han T, Hong W. The hepatocyte-specifically expressed lnc-HSER alleviates hepatic fibrosis by inhibiting hepatocyte apoptosis and epithelial-mesenchymal transition. Theranostics 2019; 9(25):7566-7582. doi:10.7150/thno.36942. Available from https://www.thno.org/v09p7566.htm

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Abstract

Graphic abstract

Liver fibrosis leading to cirrhosis is one of the major health burdens worldwide with currently limited therapeutic options available. Long noncoding RNAs (lncRNAs) play important roles in various biological and pathological processes in a cell- or tissue-specific manner. However, there is still an important gap in the understanding of the role of hepatocyte-specific lncRNAs in liver fibrosis.

Methods: The expressions of lnc-Hser in human and mice fibrotic livers as well as primary hepatocytes (HCs) of mice developing liver fibrosis were determined by real-time RT-PCR. The roles and mechanisms of lnc-Hser in HCs and liver fibrosis were determined in vitro and in vivo.

Results: In this study, we have identified a hepatocyte-specifically expressed lnc-Hser, which was reduced in human and mice fibrotic livers as well as primary HCs of mice developing liver fibrosis. We have shown that silencing lnc-Hser aggravated liver fibrosis both in vitro and in vivo through inducing the epithelial-mesenchymal transition (EMT) and the apoptosis of HCs. In addition, knockdown of lnc-Hser promoted hepatic stellate cells (HSCs) activation through the signals derived from injured HCs. Mechanistically, we have revealed that lnc-Hser inhibited HCs apoptosis via the C5AR1-Hippo-YAP pathway and suppressed HCs EMT via the Notch signaling.

Conclusions: Our work has identified a hepatocyte-specific lnc-HSER that regulates liver fibrosis, providing a proof that this molecule is a novel biomarker for damaged HCs and a potential target for anti-fibrotic therapy.

Keywords: lncRNA, liver fibrosis, hepatocyte, C5AR1, Notch