Advertisement

Hepatic aquaporin 10 expression is downregulated by activated NFκB signalling in human obstructive cholestasis

  • Author Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Min Liao
    Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Wenjing Yu
    Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China

    Marine College, Shandong University, Weihai, 264209, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Qiaoling Xie
    Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Liangjun Zhang
    Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Qiong Pan
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Nan Zhao
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Ling Li
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Ying Cheng
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Xiaoxun Zhang
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Dequn Sun
    Correspondence
    Correspondence author: Dequn Sun, Ph.D., School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010, China.
    Affiliations
    School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang, 621010 , China
    Search for articles by this author
  • Jin Chai
    Correspondence
    Correspondence author: Jin Chai, M.D., Ph.D. Professor of Gastroenterology and Hepatology, Chongqing University School of Medicine and Third Military Medical University (Army Medical University), Department of Gastroenterology, Institute of Digestive Diseases of PLA, Center for Metabolic-Associated Fatty Liver Diseases and Center for Cholestatic Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University) Chongqing, 400038, China, Tel: 86-23-68765331; Fax: 86-23-65410853.
    Affiliations
    Department of Gastroenterology

    Institute of Digestive Diseases of PLA

    Center for Cholestatic Liver Diseases and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing 400038, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors contributed equally to this study and shared the first authorship.
Open AccessPublished:November 08, 2022DOI:https://doi.org/10.1016/j.gastha.2022.11.002
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Background

      Recent studies reported that the hepatic expression of AQP8 and AQP9 was downregulated in bile duct-ligated (BDL) rats and that overexpression of human AQP1 in the rat liver attenuated cholestasis. However, the hepatic expression of AQP10 and its regulatory mechanism in human cholestasis remain unclear.

      Methods

      Serum and liver samples were collected from 34 patients with obstructive cholestasis and from 12 control patients. Eight-week-old male C57BL/6J mice were intravenously injected with an adeno‐associated virus 8 (AAV8) encoding human AQP10 driven by a hepatocyte-specific Alb promotor (AAV8-Alb promotor-hAQP10) for functional studies. Constructs of the AQP10 promoter and PLC/PRF/5-ASBT cell lines were used for regulatory mechanism studies.

      Results

      AQP10 was significantly downregulated in patients with obstructive cholestasis and negatively associated with the serum levels of total bile acid (TBA). The hepatocyte-specific overexpression of hAQP10 significantly attenuated the cholestatic liver injury and intrahepatic bile acids (BA) accumulation in BDL mice. Conjugated BAs, such as TCA and inflammatory factor TNFα, significantly repressed AQP10 expression. Furthermore, NFκB p65/p50 directly bound to the AQP10 promotor and decreased its activity in PLC/RPF/5-ASBT cells and in the livers of patients with obstructive cholestasis. However, these changes were diminished by BAY 11-7082 (a specific inhibitor of NFκB signalling).

      Conclusions

      We are the first to report that AQP10 was significantly decreased in patients with obstructive cholestasis. AQP10 overexpression significantly attenuated cholestatic liver injury in BDL mice. Therefore, overexpression of hAQP10 in the liver may be a valuable strategy for cholestasis intervention.

      Keywords

      Abbreviations:

      IF (immunofluorescence), IHC (immunohistochemistry), ChIP (chromatin Immunoprecipitation), AQP (aquaporin), NPA (asparagine-proline-alanine), DMSO (deoxycholicacid dimethyl sulfoxide), CA (Cholic acid), CDCA (chenodeoxycholic acid), GCA (glycocholate acid), GCDCA (Glycochenodeoxycholic Acid), TCA (taurocholic acid), TCDCA (Taurochenodeoxycholic acid), TDCA (taurohyodeoxycholic acid), BA (bile acid), TBA (total bile acids)