The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism

Chambel, Sílvia Sousa; Santos-Gonçalves, Andreia; Duarte, Tiago

doi:10.1155/2015/597134

Cited by 153 publications

(113 citation statements)

References 86 publications

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“…In the progression stage, cancer cells are often exposed to high levels of ROS, and their ability to escape the consequences of this is extremely important for cancer cells to survive and propagate. It has been suggested, that tumor cells could become resistant to oxidative stress, due to the activation of Nrf2 [39]. In our study, in both types of HCCs, NASH-related and HCV + , two downstream proteins of Nrf2, namely, NQO1 and SOD2, which participate in ROS elimination, were found induced, indicating that Nrf2 plays an important role in adaptation to oxidative stress in the tumor.…”

Section: Discussionsupporting

confidence: 58%

Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

Kakehashi

Стефанов

Ishii

et al. 2017

IJMS

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To uncover mechanisms of nonalcoholic steatohepatitis (NASH) associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs) and HCCs of HCV+ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained after surgery in our hospital during the period from 2006 to 2011. In addition, proteome analysis of liver tumors in male STAM NASH-model mice was performed. Similar changes in the proteome spectrum such as overexpression of enzymes involved in lipid, cholesterol and bile acid biosynthesis and examples associated with suppression of fatty acid oxidation and catabolism, alcohol metabolism, mitochondrial function as well as low expression levels of cytokeratins 8 and 18 were observed in both human NASH biopsies and NASH HCCs, but not HCV+ HCCs. Alterations in downstream protein expression pointed to significant activation of transforming growth factor β, SMAD family member 3, β-catenin, Nrf2, SREBP-LXRα and nuclear receptor-interacting protein 1 (NRIP1), and inhibition of PPARs and p53 in human NASH biopsies and/or HCCs, suggesting their involvement in accumulation of lipids, development of fibrosis, oxidative stress, cell proliferation and suppression of apoptosis in NASH hepatocarcinogenesis. In STAM mice, PPARs inhibition was not obvious, while expression of cytokeratins 8 and 18 was elevated, indicative of essential differences between human and mouse NASH pathogenesis.

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Section: Discussionsupporting

confidence: 58%

Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

Kakehashi

Стефанов

Ishii

et al. 2017

IJMS

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“…Significantly, the protein levels of Nrf2 and its major target proteins (Heme oxygenase 1 (HO1), Protein Kinase C delta (PKC-δ), NAD(P) H: Quinone Oxidoreductase 1 (NQO1) and gamma-glutamylcysteine synthetase (γ-GCS) were significantly reduced in MetKO maintained on HC diet (Chambel et al, 2015). Nrf2 down-regulation was paralleled by a coordinated activation of its repressor Keap1 while PKCδ, one of the main Nrf2 inducers (Clavijo-Cornejo et al, 2013; Niture et al, 2009), was increased, most likely as an attempt to compensate for Nrf2 down-regulation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress

et al. 2016

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Recent studies confirmed a critical importance of c-Met signaling for liver regeneration by modulating redox balance. Here we used liver-specific conditional knockout mice (MetKO) and a nutritional model of hepatic steatosis to address the role of c-Met in cholesterol-mediated liver toxicity. Liver injury was assessed by histopathology and plasma enzymes levels. Global transcriptomic changes were examined by gene expression microarray, and key molecules involved in liver damage and lipid homeostasis were evaluated by Western blotting. Loss of c-Met signaling amplified the extent of liver injury in MetKO mice fed with high-cholesterol diet for 30 days as evidenced by upregulation of liver enzymes and increased synthesis of total bile acids, aggravated inflammatory response and enhanced intrahepatic lipid deposition. Global transcriptomic changes confirmed the enrichment of networks involved in steatosis and cholestasis. In addition, signaling pathways related to glutathione and lipid metabolism, oxidative stress and mitochondria dysfunction were significantly affected by the loss of c-Met function. Mechanistically, exacerbation of oxidative stress in MetKO livers was corroborated by increased lipid and protein oxidation. Western blot analysis further revealed suppression of Erk, NF-kB and Nrf2 survival pathways and downstream target genes (e.g. cyclin D1, SOD1, gamma-GCS), as well as up-regulation of proapoptotic signaling (e.g. p53, caspase 3). Consistent with the observed steatotic and cholestatic phenotype, nuclear receptors RAR, RXR showed increased activation while expression levels of CAR, FXR and PPAR-alpha were decreased in MetKO. Collectively, our data provide evidence for the critical involvement of c-Met signaling in cholesterol and bile acids toxicity.

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“…The prevalence of NAFLD among general population has been reported as 17–33%. While it reaches as high as 75% among obese people and even more among type 2 diabetic patients …”

Section: Introductionmentioning

confidence: 99%

Inhibiting miR‐27a and miR‐142‐5p attenuate nonalcoholic fatty liver disease by regulating Nrf2 signaling pathway

et al. 2019

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Summary The gene Nrf2 (nuclear factor‐erythroid 2‐related factor 2) is the most important regulator of the cellular antioxidant system and its dysregulation has a role in the etiology of nonalcoholic fatty liver disease (NAFLD). The aim of this study was to investigate the association between Nrf2 targeted miRNAs (miR‐27a, miR‐142‐5p, miR‐153, and miR‐128) with lipid accumulation in vitro and in vivo models of NAFLD. We used two in vivo and in vitro models of NAFLD. The expression of the genes and miRNAs was assessed by real‐time PCR and the protein level was evaluated using western blot. To investigate the potential role of miRNAs in NAFLD, the inhibitors or mimics of the miR‐27a and miR‐142‐5p were transfected into HepG2 cells. The mRNA and protein levels of Nrf2 were significantly decreased in the liver of high fat diet‐fed mice as well as in HepG2 cells treated with high glucose (HG). Reduced expression of Nrf2 was associated with increased expression levels of miR‐27a and miR‐142‐5p in both models of NAFLD. HG‐induced triglyceride accumulation was attenuated by inhibition of miR‐27a or miR‐142‐5p in HepG2 cells. Overexpression of miR‐27a or miR‐142‐5p suppressed the expression of Nrf2 and its downstream antioxidant genes and increased production of reactive oxygen species, whereas inhibition of miR‐27a or miR‐142‐5p reversed these effects. In conclusion, the data of this study may suggest that miR‐27a and miR‐142‐5p are increased in NAFLD, where they suppress Nrf2 expression and contribute to the accumulation of lipids in the hepatocytes.

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The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism

Cited by 153 publications

References 86 publications

Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

Loss of c-Met signaling sensitizes hepatocytes to lipotoxicity and induces cholestatic liver damage by aggravating oxidative stress

Inhibiting miR‐27a and miR‐142‐5p attenuate nonalcoholic fatty liver disease by regulating Nrf2 signaling pathway

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