Hydrogen-rich water prevents progression of nonalcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice

Abstract

Oxidative stress is a strong contributor to the progression from simple fatty liver to nonalcoholic steatohepatitis (NASH). Molecular hydrogen is an effective antioxidant that reduces cytotoxic reactive oxygen species. In this study, we investigated the effects of hydrogen-rich water and the drug pioglitazone on the progression of NASH in mouse models. A methionine-choline-deficient (MCD) diet mouse model was prepared. Mice were divided into three experimental groups and fed for 8 weeks as follows: (1) MCD diet 1 control water (CW group); (2) MCD diet 1 hydrogen-rich water (HW group); and (3) MCD diet mixed with pioglitazone (PGZ group). Plasma alanine aminotransferase levels, hepatic expression of tumor necrosis factor-a, interleukin-6, fatty acid synthesis-related genes, oxidative stress biomarker 8-hydroxydeoxyguanosine (8-OHdG), and apoptosis marker terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nickend labeling (TUNEL)-positive cells in the liver were decreased in the HW and PGZ groups. The HW group showed a smaller decrease in hepatic cholesterol; however, stronger antioxidative effects in serum and lower peroxisome proliferator-activated receptor-a expression in the liver were seen in comparison with the PGZ group. We then investigated the effects of hydrogen in the prevention of hepatocarcinogenesis in STAM mice, known as the NASH-related hepatocarcinogenesis model. Eight-week-old male STAM mice were divided into three experimental groups as follows: (1) control water (CW-STAM); (2) hydrogen-rich water (HW-STAM); and (3) pioglitazone (PGZ-STAM). After 8 weeks, hepatic tumors were evaluated. The number of tumors was significantly lower in the HW-STAM and PGZ-STAM groups than in the CW-STAM group. The maximum tumor size was smaller in the HW-STAM group than in the other groups. Conclusion: Consumption of hydrogen-rich water may be an effective treatment for NASH by reducing hepatic oxidative stress, apoptosis, inflammation, and hepatocarcinogenesis. (HEPATOLOGY 2012;56:912-921)

Molecular Mechanisms and New Treatment Strategies for Non-Alcoholic Steatohepatitis (NASH)

“…Excessive oxidative stress induced by mitochondrial, peroxisomal and microsomal reactive oxygen species (ROS) in NASH results in apoptosis as well as damage to nuclear and mitochondrial DNA. Limited antioxidant defenses contribute to the processes of both NASH and hepatocarcinogenesis [74,75]. Physiologically low levels of ROS are involved in necessary vital cellular processes indicating that the balance of oxidative-antioxidative responses is important [76].…”

“…Kawai et al reported that drinking hydrogen-rich water has favorable effects in NASH models [74]. Plasma transaminase levels, histological NAS, hepatic TNF-α, IL-6 and fatty acid synthesis-related gene expression and the oxidative stress biomarker 8-OHdG were decreased in the livers of established MCD diet-induced NASH models administered hydrogen-rich water or the antioxidant pioglitazone.…”

A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance

“…STAM mice, which develop steatohepatitis, cirrhosis and carcinoma in progression starting treatment with streptozotocin at day 2 and feeding the HFC diet at 4 weeks, develop NASH at 8 weeks and cancer at 16 weeks. 11 However, in these models no significant insulin resistance develops, which insufficiently reflects the pathogenesis of NASH in patients as a component/complication of obesity, diabetes and metabolic syndrome.…”

Potential ghrelin-mediated benefits and risks of hydrogen water

“…Patients with chronic hepatitis C who achieved a sustained virological response to therapy tended to have higher ghrelin levels [113]. Administration of hydrogen water has likewise proved protective in mouse models of liver injury induced by a methionine-choline deficient diet, or by injection of carbon tetrachloride or tetracetamide; inflammation, fibrosis and hepatocarcinogenesis were inhibited by hydrogen water in these studies [114,115]. A controlled pilot clinical trial of hydrogen water in patients chronically infected with hepatitis C observed a significant reduction of markers of oxidative stress in those receiving the hydrogen water; liver function and HCV DNA levels also declined in this group, although this benefit did not achieve statistical significance relative to the group not receiving the water [116].…”