Thrombospondin 2 is a key determinant of fibrogenesis in non‐alcoholic fatty liver disease

Author:

Kimura Takefumi12ORCID,Iwadare Takanobu1,Wakabayashi Shun‐ichi1,Kuldeep Seema3,Nakajima Tomoyuki4,Yamazaki Tomoo15,Aomura Daiki6,Zafar Hamim7,Iwaya Mai4,Joshita Satoru1,Uehara Takeshi4,Pydi Sai P.3,Tanaka Naoki8910,Umemura Takeji12ORCID

Affiliation:

1. Department of Medicine, Division of Gastroenterology and Hepatology Shinshu University School of Medicine Matsumoto Japan

2. Consultation Center for Liver Diseases Shinshu University Hospital Matsumoto Japan

3. Department of Biological Sciences and Bioengineering Indian Institute of Technology Kanpur India

4. Department of Laboratory Medicine Shinshu University School Hospital Matsumoto Japan

5. Department of Medicine University of California San Diego San Diego La Jolla USA

6. Department of Medicine, Division of Nephrology Shinshu University School of Medicine Matsumoto Japan

7. Department of Computer Science and Engineering and Biological Sciences and Bioengineering Indian Institute of Technology Kanpur India

8. Department of Global Medical Research Promotion Shinshu University Graduate School of Medicine Matsumoto Japan

9. International Relations Office Shinshu University School of Medicine Matsumoto Japan

10. Research Center for Social Systems Shinshu University Matsumoto Japan

Abstract

AbstractObjectiveHepatic overexpression of the thrombospondin 2 gene (THBS2) and elevated levels of circulating thrombospondin 2 (TSP2) have been observed in patients with chronic liver disease. This study aimed to identify the specific cells expressing THBS2/TSP2 in non‐alcoholic fatty liver disease (NAFLD) and investigate the underlying mechanism behind THBS2/TSP2 upregulation.DesignComprehensive NAFLD liver gene datasets, including single‐cell RNA sequencing (scRNA‐seq), in‐house NAFLD liver tissue, and LX‐2 cells derived from human hepatic stellate cells (HSCs), were analysed using a combination of computational biology, genetic, immunological, and pharmacological approaches.ResultsAnalysis of the genetic dataset revealed the presence of 1433 variable genes in patients with advanced fibrosis NAFLD, with THBS2 ranked among the top 2 genes. Quantitative polymerase chain reaction (qPCR) examination of NAFLD livers showed a significant correlation between THBS2 expression and fibrosis stage (r = .349, p < .001). In support of this, scRNA‐seq data and in situ hybridization demonstrated that the THBS2 gene was highly expressed in HSCs of NAFLD patients with advanced fibrosis. Pathway analysis of the gene dataset revealed THBS2 expression to be associated with the transforming growth factor beta (TGFβ) pathway and collagen gene activation. Moreover, the activation of LX‐2 cells with TGFβ increased THBS2/TSP2 and collagen expression independently of the TGFβ‐SMAD2/3 pathway. THBS2 gene knockdown significantly decreased collagen expression in LX‐2 cells.ConclusionsTHBS2/TSP2 is highly expressed in HSCs and plays a role in regulating fibrogenesis in NAFLD patients. THBS2/TSP2 may therefore represent a potential target for anti‐fibrotic therapy in NAFLD.

Funder

Japan Agency for Medical Research and Development

Indian Council of Medical Research

Publisher

Wiley

Subject

Hepatology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3