Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

Satapati, Santhosh; Kucejová, Blanka; Duarte, João; Fletcher, Justin A.; Reynolds, Lacy; Sunny, Nishanth E.; He, TianTeng; Nair, Lawrence; Livingston, Kenneth A.; Fu, Xiaorong; Merritt, Matthew E.; Sherry, A. Dean; Malloy, Craig R.; Shelton, John M.; Lambert, Jessica E.; Parks, Elizabeth J.; Corbin, Ian R.; Magnuson, Mark A.; Browning, Jeffrey D.; Burgess, Shawn C.

doi:10.1172/jci86695

Cited by 87 publications

(110 citation statements)

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“…Based on accumulation evidence, excess lipid accumulation promotes lipotoxicity and may induce hepatic injury and inflammation in mice by generating oxidative stress [19, 20]. In addition, oxidative stress participates in the inflammatory response to liver disease in a variety of human conditions and experimental animal models [21, 22].…”

Section: Discussionmentioning

confidence: 99%

Elevated Apoptosis in the Liver of Dairy Cows with Ketosis

Chen

Huang

et al. 2017

Cell Physiol Biochem

102

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Background/Aims: Dairy cows with ketosis are characterized by oxidative stress and hepatic damage. The aim of this study was to investigate hepatic oxidative stress and the apoptotic status of ketotic cows, as well as the underlying apoptosis pathway. Methods: The blood aspartate aminotransferase (AST), alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH) and gamma-glutamyl transferase (GGT) activities and the haptoglobin (HP), serum amyloid A (SAA) and serum apoptotic cytokeratin 18 neo-epitope M30 (CK18 M30) concentrations were determined by commercially available kits and ELISA kits, respectively. Liver histology, TUNEL and Oil red O staining were performed in liver tissue samples. TG contents were measured using an enzymatic kit; Caspase 3 assays were carried out using the Caspase 3 activity assay kit; oxidation and antioxidant markers were measured using biochemical kits; apoptosis pathway were determined by qRT-PCR and western blot. Results: Ketotic cows displayed hepatic fat accumulation. The hepatic malondialdehyde (MDA) content was significantly increased, but the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were markedly decreased in ketotic cows compared with control cows, indicating that ketotic cows displayed severe oxidative stress. Significantly higher serum levels of the hepatic damage markers AST, ALT, GGT and GLDH were observed in ketotic cows than in control cows. The blood concentration of the apoptotic marker CK18 M30 and the number of TUNEL-positive cells in the liver of ketotic cows were 1.19- and 2.61-fold, respectively, higher than the values observed in control cows. Besides, Caspase 3 activity was significantly increased in the liver of ketosis cows. Importantly, the levels of phosphorylated c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK) were significantly increased but the level of phosphorylated extracellular signal-regulated kinase1/2 (ERK1/2) was markedly decreased, which further promoted tumor protein 53 (p53) expression and inhibited nuclear factor E2-related factor 2 (Nrf2) expression. The apoptosis-related molecules p21, MDM2, Caspase 3, Caspase 9 and Bax were expressed at significantly higher levels in ketotic cows than in healthy cows, whereas the anti-apoptosis molecule Bcl-2 was expressed at significantly lower levels. Conclusions: Based on these results, ketotic cows display severe hepatic oxidative stress. The hepatic MAPK-p53-Nrf2 apoptotic pathway is over induced and partially mediated apoptotic damage in the liver.

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Section: Discussionmentioning

confidence: 99%

Elevated Apoptosis in the Liver of Dairy Cows with Ketosis

Chen

Huang

et al. 2017

Cell Physiol Biochem

102

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“…Metformin has also been shown to partially attenuate gut dysbiosis caused by disease . Furthermore, many studies have shown that metformin has anti‐inflammatory effects in vitro and in vivo . Specifically, some studies have reported that metformin can attenuate intestinal inflammation in mice with colitis .…”

Section: Introductionmentioning

confidence: 99%

Metformin protects against intestinal barrier dysfunction via AMPKα1‐dependent inhibition of JNK signalling activation

Deng

Zeng

Lai

et al. 2017

J Cellular Molecular Medi

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Disruption of the intestinal epithelial barrier, that involves the activation of C‐Jun N‐terminal kinase (JNK), contributes to initiate and accelerate inflammation in inflammatory bowel disease. Metformin has unexpected beneficial effects other than glucose‐lowering effects. Here, we provided evidence that metformin can protect against intestinal barrier dysfunction in colitis. We showed that metformin alleviated dextran sodium sulphate (DSS)‐induced decreases in transepithelial electrical resistance, FITC‐dextran hyperpermeability, loss of the tight junction (TJ) proteins occludin and ZO‐1 and bacterial translocation in Caco‐2 cell monolayers or in colitis mice models. Metformin also improved TJ proteins expression in ulcerative colitis patients with type 2 diabetes mellitus. We found that metformin ameliorated the induction of colitis and reduced the levels of pro‐inflammatory cytokines IL‐6, TNF‐a and IL‐1β. In addition, metformin suppressed DSS‐induced JNK activation, an effect dependent on AMP‐activated protein kinase α1 (AMPKα1) activation. Consistent with this finding, metformin could not maintain the barrier function of AMPKα1‐silenced cell monolayers after DSS administration. These findings highlight metformin protects against intestinal barrier dysfunction. The potential mechanism may involve in the inhibition of JNK activation via an AMPKα1‐dependent signalling pathway.

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“…Oxidative stress (OS) is a condition of imbalance between the antioxidant defense mechanisms and the production of free radicals, which favors the latter, leading to potential damage (6). OS is one of the major contributors to the pathogenesis of NAFLD (7). Increased accumulation of liver TGs may cause increased OS in the hepatocytes of animals and humans (8).…”

Section: Introductionmentioning

confidence: 99%

Influence of different concentrations of uric acid on oxidative stress in steatosis hepatocytes

Cheng

Yang²,

Zhou

et al. 2018

Exp Ther Med

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Abstract. The development of nonalcoholic fatty liver disease (NAFLD) is caused by the steatosis of hepatocytes, which induces oxidative stress (OS). Thus, OS has an important role in the development of NAFLD. In the present study, the L-02 hepatocyte cell line was used to develop a steatosis cell model. The best model was determined using an MTT assay and the triglyceride levels. Model cells were treated with high concentrations of uric acid (UA; 0, 5, 10, 20 and 30 mg/dl) for 24, 48, 72 and 96 h. Indicators of oxidation were then measured, which included total superoxide dismutase (SOD), malonaldehyde (MDA) and reduced glutathione (GSH), and the transcriptional and translational levels of SOD1 and γ-glutamate-cysteine ligase (γ-GCLC) were also determined. In addition, the intracellular levels of aspartate aminotransferase and alanine aminotransferase (ALT) were detected. The activity of SOD1 decreased over time and the result was supported by the results of western blotting. The transcriptional levels of SOD1 in model cells was significantly higher than untreated cells at 48 h. With the decreased levels of SOD1 and GSH, MDA increased in a time-dependent manner. The content of GSH decreased with time as well, which was also reflected in the results of western blotting. The transcriptional levels of γ-GCLC in all UA-treated groups were lower when compared with those observed in the model group. The activity of ALT tended to increase, depending on the duration of treatment. Treatment with 5 and 10 mg/dl UA had an antioxidative effect on the model cells, and 30 mg/dl UA treatment for 48 h increased OS in the cells.

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Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver

Abstract: A r t i c l e A m e n d m e n t s 1 6 0 5

Cited by 87 publications

References 0 publications

Elevated Apoptosis in the Liver of Dairy Cows with Ketosis

Elevated Apoptosis in the Liver of Dairy Cows with Ketosis

Metformin protects against intestinal barrier dysfunction via AMPKα1‐dependent inhibition of JNK signalling activation

Influence of different concentrations of uric acid on oxidative stress in steatosis hepatocytes

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