Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease

Sumida, Yoshio; Nakashima, Tomoki; Yoh, Takaharu; Furutani, Masanori; Hirohama, Akihisa; Kakisaka, Yuko; Nakajima, Yoshiki; Ishikawa, Hiroki; Mitsuyoshi, Hironori; Okanoue, Takeshi; Kashima, Kei; Nakamura, Hajime; Yodoi, Junji

doi:10.1016/s0168-8278(02)00331-8

Cited by 189 publications

(131 citation statements)

References 39 publications

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“…Serum ferritin and thioredoxin levels, the surrogate markers reflecting hepatic oxidative stress at least in part, 24,28 significantly dropped after EPA treatment. EPA administration to mice has been found to markedly reduce hepatic malondialdehyde and 4-hydroxynonenal contents through enhanced expression of copper, zinc, and manganese-superoxide dismutases (Tanaka N and Aoyama T, unpublished results).…”

Section: Discussionmentioning

confidence: 98%

“…Although serum iron concentrations and transferrin saturation ratios remained unchanged, serum ferritin concentrations were significantly reduced after 12 months (46% decrease, P<0.001). Serum thioredoxin levels, which is known to be elevated with an increase in hepatic oxidative stress, 24 were also decreased (27% decrease, P=0.036).…”

Section: Effect Of Epa On Biochemical Parametersmentioning

confidence: 97%

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Highly Purified Eicosapentaenoic Acid Treatment Improves Nonalcoholic Steatohepatitis

Tanaka¹,

Sakai

Horiuchi

et al. 2008

Journal of Clinical Gastroenterology

213

160

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Section: Discussionmentioning

confidence: 98%

Section: Effect Of Epa On Biochemical Parametersmentioning

confidence: 97%

Highly Purified Eicosapentaenoic Acid Treatment Improves Nonalcoholic Steatohepatitis

Tanaka¹,

Sakai

Horiuchi

et al. 2008

Journal of Clinical Gastroenterology

213

160

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“…An important factor in the progression of NAFLD is oxidative stress, with NAFLD patients being reported to have increased oxidative stress (Sumida et al 2003, Yesilova et al 2005) and a decrease in antioxidant defenses (Videla et al 2004). T2DM is also characterized by the presence of oxidative stress (Davi et al 1999), and diabetic patients with NAFLD have higher levels of markers of oxidative stress compared to diabetic patients without NAFLD (Narasimhan et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

Yin¹,

Zheng²,

Pan³

et al. 2015

Journal of Molecular Endocrinology

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Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 mmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.

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“…Accumulating evidence suggests that oxidative stress is the necessary "second hit" to trigger liver injuries in NASH (4,5). Indeed, NASH in both humans and rodents is associated with increased oxidative stress and decreased activities of antioxidant enzymes (6)(7)(8)(9)(10). SOD2 is one of the primary antioxidant enzymes in the mitochondria, which is the principal source of cellular ROS.…”

Section: Discussionmentioning

confidence: 99%

“…Overwhelming oxidative stress causes cell membrane lipid peroxidation and hepatic stellate cell activation, leading to the exhibition of the hallmarks of NASH, such as fibrosis, chronic inflammation, and apoptosis. Indeed, increased levels of serum oxidants and decreased antioxidant defense have been reported in NASH in both humans and rodents (6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Activation of the Aryl Hydrocarbon Receptor Sensitizes Mice to Nonalcoholic Steatohepatitis by Deactivating Mitochondrial Sirtuin Deacetylase Sirt3

Shi

et al. 2013

Molecular and Cellular Biology

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Nonalcoholic steatohepatitis (NASH) is a liver disorder that still demands improved treatment. Understanding the pathogenesis of NASH will help to develop novel approaches to prevent or treat this disease. In this study, we revealed a novel function of the aryl hydrocarbon receptor (AhR) in NASH. Transgenic or pharmacological activation of AhR heightened animal sensitivity to NASH induced by the methionine-and choline-deficient (MCD) diet, which was reasoned to be due to increased hepatic steatosis, production of reactive oxygen species (ROS), and lipid peroxidation. Mechanistically, the increased ROS production in AhRactivated mouse liver was likely a result of a lower superoxide dismutase 2 (SOD2) activity and compromised clearance of ROS. Activation of AhR induced tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly(ADP-ribose) polymerase (TiPARP) gene expression, depleted NAD؉ , deactivated the mitochondrial sirtuin deacetylase 3 (Sirt3), increased SOD2 acetylation, and thereby decreased SOD2 activity. We also showed that Sirt3 ablation sensitized mice to NASH, whereas adenoviral overexpression of Sirt3 alleviated the NASH phenotype in AhR-transgenic mice. We conclude that activation of AhR sensitizes mice to NASH by facilitating both the "first hit" of steatosis and the "second hit" of oxidative stress. Our results suggest that the use of AhR antagonists might be a viable approach to prevent and treat NASH. Manipulation of the expression or activity of Sirt3 may also represent a novel approach to manage NASH.

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Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease

Cited by 189 publications

References 39 publications

Highly Purified Eicosapentaenoic Acid Treatment Improves Nonalcoholic Steatohepatitis

Highly Purified Eicosapentaenoic Acid Treatment Improves Nonalcoholic Steatohepatitis

Glucose fluctuation increased hepatocyte apoptosis under lipotoxicity and the involvement of mitochondrial permeability transition opening

Activation of the Aryl Hydrocarbon Receptor Sensitizes Mice to Nonalcoholic Steatohepatitis by Deactivating Mitochondrial Sirtuin Deacetylase Sirt3

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