Nitric Oxide Plays a Crucial Role in the Development/Progression of Nonalcoholic Steatohepatitis in the Choline-Deficient, l-Amino Acid-Defined Diet-Fed Rat Model
Koji Fujita
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorYuichi Nozaki
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorMasato Yoneda
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorKoichiro Wada
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorHirokazu Takahashi
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorHiroyuki Kirikoshi
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorMasahiko Inamori
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorSatoru Saito
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorTomoyuki Iwasaki
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorYasuo Terauchi
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorShiro Maeyama
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorAtsushi Nakajima
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorKoji Fujita
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorYuichi Nozaki
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorMasato Yoneda
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorKoichiro Wada
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorHirokazu Takahashi
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorHiroyuki Kirikoshi
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorMasahiko Inamori
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorSatoru Saito
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorTomoyuki Iwasaki
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorYasuo Terauchi
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorShiro Maeyama
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorAtsushi Nakajima
From the Division of Gastroenterology, Yokohama City University Graduate School of Medicine (KF, YN, MY, HT, HK, MI, SS, AN), Yokohama; Department of Pharmacology, Graduate School of Density, Osaka University (KW), Osaka; Division of Endocrinology and Metabolism, Yokohama City University Graduate School of Medicine (TI, YT), Yokohama; and Kitakashiwa Rehabilitation Hospital (SM), Chiba, Japan.
Search for more papers by this authorAbstract
Background: The pathogenesis of nonalcoholic steatohepatitis (NASH) is still unclear. Recently, the 2-hit hypothesis was proposed, in which nitric oxide production, representing oxidative stress, was proposed as a very important candidate for the second hit.
Methods: The total study period was 10 weeks. A total of 20 rats were randomly divided into 2 groups. Group 1 was administered the Choline-Deficient, l-Amino Acid-Defined diet to produce a NASH model, and Group 2 as control received the Choline-Sufficient, l-Amino Acid-defined diet. The blood and tissue concentrations of nitrate + nitrite were measured using the Griess reagent and the expression levels of inducible nitric oxide synthase (iNOS) proteins and mRNA was determined by Western blotting.
Results: In regard to nitric oxide (NO) and NO metabolites, there were significant differences in the blood (especially portal venous blood) as well as tissue (liver and visceral fat) concentrations between the 2 animal groups; the amounts of NO metabolites in the tissues were much higher in the NASH models. The level of nitrotyrosine was much markedly higher in the NASH models than in the controls. In regard to the tissue expression of iNOS a significant difference between the 2 groups was found in the visceral fat, especially in the mesenterium.
Conclusions: Based on these results, we hypothesize that the iNOS expression and NO levels in the visceral fat increase, with increased diffusion of NO and its metabolites into the liver, resulting in increased nitrotyrosine formation in the liver; this, in turn, induces inflammation, apoptosis, and fibrosis in the liver, which are one of the characteristic features of NASH.
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