Research ArticleLiver and Biliary Tract Physiology/Pathophysiology

Hydrogen-rich water protects against liver injury in nonalcoholic steatohepatitis through HO-1 enhancement via IL-10 and Sirt 1 signaling

Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, China

Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

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Terumi Takahara

Third Department of Internal Medicine, University of Toyama, Toyama, Japan

Correspondence: X-K. Li ([email protected]).

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Weitao Que

Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

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Masayuki Fujino

Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan

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Wen-Zhi Guo

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

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Shin-Ichi Hirano

MiZ Co., Ltd., Kanagawa, Japan

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Li-Ping Ye

Department of Gastroenterology, Taizhou Hospital of Zhejiang Province affiliated to Wenzhou Medical University, Taizhou, China

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, and

Xiao-Kang Li

Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan

Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

Correspondence: X-K. Li ([email protected]).

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Published Online:01 Apr 2021https://doi.org/10.1152/ajpgi.00158.2020

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Abstract

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Nonalcoholic steatohepatitis (NASH) could progress to hepatic fibrosis in the absence of effective control. The purpose of our experiment was to investigate the protective effect of drinking water with a high concentration of hydrogen, namely, hydrogen-rich water (HRW), on mice with nonalcoholic fatty liver disease to elucidate the mechanism underlying the therapeutic action of molecular hydrogen. The choline-supplemented, l-amino acid-defined (CSAA) or the choline-deficient, l-amino acid-defined (CDAA) diet for 20 wk was used to induce NASH and fibrosis in the mice model and simultaneously treated with the high-concentration 7-ppm HRW for different periods (4 wk, 8 wk, and 20 wk). Primary hepatocytes were stimulated by palmitate to mimic liver lipid metabolism during fatty liver formation. Primary hepatocytes were cultured in a closed vessel filled with 21% O₂ + 5% CO₂ + 3.8% H₂ and N₂ as the base gas to verify the response of primary hepatocytes in a high concentration of hydrogen gas in vitro. Mice in the CSAA + HRW group had lower serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and milder histological damage. The inflammatory cytokines were expressed at lower levels in the HRW group than in the CSAA group. Importantly, HRW reversed hepatocyte fatty acid oxidation and lipogenesis as well as hepatic inflammation and fibrosis in preexisting hepatic fibrosis specimens. Molecular hydrogen inhibits the lipopolysaccharide-induced production of inflammation cytokines through increasing heme oxygenase-1 (HO-1) expression. Furthermore, HRW improved hepatic steatosis in the CSAA + HRW group. Sirtuin 1 (Sirt1) induction by molecular hydrogen via the HO-1/adenosine monophosphate activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα)/peroxisome proliferator-activated receptor γ (PPAR-γ) pathway suppresses palmitate-mediated abnormal fat metabolism. Orally administered HRW suppressed steatosis induced by CSAA and attenuated fibrosis induced by CDAA, possibly by reducing oxidative stress and the inflammation response.

NEW & NOTEWORTHY The mRNA expression of inflammatory cytokines in the HRW group was lower than in the CSAA group. HRW reversed hepatocyte apoptosis as well as hepatic inflammation and fibrosis in NASH specimens. Molecular hydrogen inhibits LPS-induced inflammation via an HO-1/interleukin 10 (IL-10)-independent pathway. HRW improved hepatic steatosis in the CSAA + HRW group. Sirt1 induction by molecular hydrogen via the HO-1/AMPK/PPARα/PPARγ pathway suppresses palmitate-mediated abnormal fat metabolism.

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