Clinicopathological significance of oxidative cellular damage in non-alcoholic fatty liver diseases

Seki, Shuichi; Kitada, Takuya; Sakaguchi, Hiroki

doi:10.1016/j.hepres.2005.09.020

Cited by 84 publications

(59 citation statements)

References 10 publications

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“…Because increased oxidative stress is often observed in human and experimental models of steatohepatitis (Chalasani et al, 2004;Seki et al, 2005), we next determined the levels of ROS production in OA-or PA-treated cells in the presence or absence of the antioxidant NAC. NAC has been widely used as an antioxidant and has been shown to block autophagy in many experimental models (Scherz-Shouval et al, 2007;Ding et al, 2010b).…”

Section: Resultsmentioning

confidence: 99%

Differential Roles of Unsaturated and Saturated Fatty Acids on Autophagy and Apoptosis in Hepatocytes

Mei

Manley

et al. 2011

J Pharmacol Exp Ther

264

219

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Fatty acid-induced lipotoxicity plays a critical role in the pathogenesis of nonalcoholic liver disease. Saturated fatty acids and unsaturated fatty acids have differential effects on cell death and steatosis, but the mechanisms responsible for these differences are not known. Using cultured HepG2 cells and primary mouse hepatocytes, we found that unsaturated and saturated fatty acids differentially regulate autophagy and apoptosis. The unsaturated fatty acid, oleic acid, promoted the formation of triglyceride-enriched lipid droplets and induced autophagy but had a minimal effect on apoptosis. In contrast, the saturated fatty acid, palmitic acid, was poorly converted into triglyceride-enriched lipid droplets, suppressed autophagy, and significantly induced apoptosis. Subsequent studies revealed that palmitic acid-induced apoptosis suppressed autophagy by inducing caspase-dependent Beclin 1 cleavage, indicating cross-talk between apoptosis and autophagy. Moreover, our data suggest that the formation of triglyceride-enriched lipid droplets and induction of autophagy are protective mechanisms against fatty acid-induced lipotoxicity. In line with our in vitro findings, we found that high-fat diet-induced hepatic steatosis was associated with autophagy in the mouse liver. Potential modulation of autophagy may be a novel approach that has therapeutic benefits for obesity-induced steatosis and liver injury.

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Section: Resultsmentioning

confidence: 99%

Differential Roles of Unsaturated and Saturated Fatty Acids on Autophagy and Apoptosis in Hepatocytes

Mei

Manley

et al. 2011

J Pharmacol Exp Ther

264

219

View full text Add to dashboard Cite

show abstract

“…The liver injury in ALD is dependent on the metabolic product of ethanol (acetaldehyde) causing functional and metabolic derangements [7] along with induction of cytochrome P450 2E1 (CYP450 2E1) that results in increased generation of reactive oxygen species (ROS) and development of OS [8]. In NAFLD also, oxidative damage has been proposed as a mechanism of lipid peroxidation and inflammatory recruitment resulting in progression of disease along with antioxidant enzyme modification [9][10][11][12][13]. Biochemical and histological improvement after treatment with antioxidants in NAFLD is an indirect evidence of OSinduced pathogenesis [14].…”

Section: Introductionmentioning

confidence: 99%

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

et al. 2008

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Purpose Altered redox status has been implicated in pathogenesis of alcoholic liver disease (ALD) as well as in nonalcoholic fatty liver disease (NAFLD). This study was planned to find the relative role of redox status in these two diseases. Methods A total of 44 patients with ALD and 32 patients with NAFLD and 25 apparently healthy controls were included in the study. Redox status was estimated by measuring oxidative stress (superoxide dismutase (SOD) and lipid peroxidation products as thiobarbituric acid reactive substances (TBARS)) and antioxidant status (ferric reducing ability of plasma (FRAP) and vitamin C). Results TBARS level was raised significantly in both ALD (3.5 (2.3-9.4) vs. 1.8 (0.5-4.1) nmol/ml; P = 0.0001) and NAFLD (5.1 (1-10.2) vs. 1.82 (0.51-4.1) nmol/ml; P = 0.0001) as compared with controls, but was not different between ALD and NAFLD. SOD was significantly higher in ALD as compared to NAFLD (2.4 (1.3-7.8) vs. 0.68 (0.05-19.1) U/ml; P = 0.0001) and controls (1.12 (0.01-3.5) U/ml; P = 0.001). FRAP was lower in ALD as compared with 3) lmol of Fe +2 liberated; P = 0.001) but similar to that of controls (340.9 (141.5-697.5) lmol of Fe +2 liberated). Conclusions ALD patients have a higher degree of redox imbalance as compared with NAFLD patients

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“…It has been reported that hepatic thiobarbital acid reactive substances (TBARSs) and 8-hydroxydeoxyguanosine (8-OHdG), as reliable markers of lipid peroxidation and oxidative DNA-damage, respectively, were significantly increased both in the animal models and human samples of NASH. [6][7][8] However, it is not known whether reactive oxygen species can result in progression of liver fibrosis and hepatocarcinogenesis, beccause, like diabetes mellitus, NASH is almost certainly a polygenic disease affected by several factors, with disease pathogenesis related to multiple "hits." 3 Animal models of hepatic steatosis and steatohepatitis have improved the understanding of the pathogenesis of NASH.…”

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confidence: 99%

Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats

et al. 2006

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Nonalcoholic steatohepatitis (NASH) may cause fibrosis, cirrhosis, and hepatocellular carcinoma (HCC); however, the exact mechanism of disease progression is not fully understood. Angiogenesis has been shown to play an important role in the progression of chronic liver disease. The aim of this study was to elucidate the role of angiogenesis in the development of liver fibrosis and hepatocarcinogenesis in NASH. Zucker rats, which naturally develop leptin receptor mutations, and their lean littermate rats were fed a choline-deficient, amino acid-defined diet. Both Zucker and littermate rats showed marked steatohepatitis and elevation of oxidative stress markers (e.g., thiobarbital acid reactive substances and 8-hydroxydeoxyguanosine). In sharp contrast, liver fibrosis, glutathione-S-transferase placental form (GST-P)-positive preneoplastic lesions, and HCC developed in littermate rats but not in Zucker rats. Hepatic neovascularization and the expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, only increased in littermate rats, almost in parallel with fibrogenesis and carcinogenesis. The CD31-immunopositive neovessels were mainly localized either along the fibrotic septa or in the GST-P-positive lesions. Our in vitro study revealed that leptin exerted a proangiogenic activity in the presence of VEGF. In conclusion, these results suggest that leptin-mediated neovascularization coordinated with VEGF plays an important role in the development of liver fibrosis and hepatocarcinogenesis in NASH. Supplementary material for this article can be found on the HEPATOLOGY website

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Clinicopathological significance of oxidative cellular damage in non-alcoholic fatty liver diseases

Cited by 84 publications

References 10 publications

Differential Roles of Unsaturated and Saturated Fatty Acids on Autophagy and Apoptosis in Hepatocytes

Differential Roles of Unsaturated and Saturated Fatty Acids on Autophagy and Apoptosis in Hepatocytes

Comparative redox status in alcoholic liver disease and nonalcoholic fatty liver disease

Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats

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