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.
Am J Physiol Gastrointest Liver Physiol. 2021 Apr 1;320(4):G450-G463. doi: 10.1152/ajpgi.00158.2020. Epub 2021 Jan 13.
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% O + 5% CO + 3.8% H and N 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. 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.
非酒精性脂肪性肝炎（NASH）如果得不到有效控制可能会进展为肝纤维化。本实验的目的是研究高浓度氢气水（HRW）对非酒精性脂肪肝小鼠的保护作用，以阐明分子氢的治疗作用机制。采用胆碱补充型、必需氨基酸定义型（CSAA）或胆碱缺乏型、必需氨基酸定义型（CDAA）饮食 20 周诱导小鼠模型发生 NASH 和纤维化，并同时用高浓度 7ppm HRW 进行不同时间（4 周、8 周和 20 周）治疗。用棕榈酸刺激原代肝细胞模拟脂肪肝形成过程中的肝脂质代谢。将原代肝细胞在充满 21%O+5%CO+3.8%H 和 N 的封闭容器中培养，以验证原代肝细胞在高浓度氢气中的反应。CSAA+HRW 组小鼠血清丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平较低，组织学损伤较轻。HRW 组炎症细胞因子的表达水平低于 CSAA 组。重要的是，HRW 逆转了肝纤维化标本中肝细胞的脂肪酸氧化和脂肪生成以及肝炎症和纤维化。分子氢通过增加血红素加氧酶-1（HO-1）的表达抑制脂多糖诱导的炎症细胞因子的产生。此外，HRW 改善了 CSAA+HRW 组的肝脂肪变性。分子氢通过 HO-1/腺苷单磷酸激活蛋白激酶（AMPK）/过氧化物酶体增殖物激活受体α（PPARα）/过氧化物酶体增殖物激活受体γ（PPAR-γ）通路诱导 Sirtuin 1（Sirt1），抑制棕榈酸介导的异常脂肪代谢。口服 HRW 抑制 CSAA 诱导的脂肪变性，并减轻 CDAA 诱导的纤维化，可能通过减少氧化应激和炎症反应。HRW 组的炎症细胞因子 mRNA 表达低于 CSAA 组。HRW 逆转了 NASH 标本中肝细胞凋亡以及肝炎症和纤维化。分子氢通过 HO-1/白细胞介素 10（IL-10）非依赖性途径抑制 LPS 诱导的炎症。HRW 改善了 CSAA+HRW 组的肝脂肪变性。分子氢通过 HO-1/AMPK/PPARα/PPARγ 通路诱导 Sirt1，抑制棕榈酸介导的异常脂肪代谢。
