Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte‐Specific c‐met Deletion during the Progression of NASH

Abstract

We have recently shown that hepatocyte-specific c-met deficiency accelerates the progression of nonalcoholic steatohepatitis in experimental murine models resulting in augmented production of reactive oxygen species and accelerated development of fibrosis. The aim of this study focuses on the elucidation of the underlying cellular mechanisms driven by Nrf2 overactivation in hepatocytes lacking c-met receptor characterized by a severe unbalance between pro-oxidant and antioxidant functions. Control mice (c-metfx/fx), single c-met knockouts (c-metΔhepa), and double c-met/Keap1 knockouts (met/Keap1Δhepa) were then fed a chow or a methionine-choline-deficient (MCD) diet, respectively, for 4 weeks to reproduce the features of nonalcoholic steatohepatitis. Upon MCD feeding, met/Keap1Δhepa mice displayed increased liver mass albeit decreased triglyceride accumulation. The marked increase of oxidative stress observed in c-metΔhepa was restored in the double mutants as assessed by 4-HNE immunostaining and by the expression of genes responsible for the generation of free radicals. Moreover, double knockout mice presented a reduced amount of liver-infiltrating cells and the exacerbation of fibrosis progression observed in c-metΔhepa livers was significantly inhibited in met/Keap1Δhepa. Therefore, genetic activation of the antioxidant transcription factor Nrf2 improves liver damage and repair in hepatocyte-specific c-met-deficient mice mainly through restoring a balance in the cellular redox homeostasis.

Indole-3-Carbinol Derivative DIM Mitigates Carbon Tetrachloride-Induced Acute Liver Injury in Mice by Inhibiting Inflammatory Response, Apoptosis and Regulating Oxidative Stress

“…Nrf2/HO-1 cascade has found to be a protective master regulator against liver disease through the means of cellular defense by mediating antioxidant response and anti-inflammatory and cytoprotective properties. Loss or dysregulation of Nrf2/HO-1 activity was found to be correlated with the development of chronic inflammatory diseases [12][13][14][15][16]. Therefore, antioxidant and anti-inflammatory therapies are proposed to prevent and treat liver injury.…”

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

“…In addition, transgenic mice expressing Nrf2 in hepatocytes and fed an MCD diet during 28 days showed increased expression of genes involved in triglyceride export, such as Microsomal Triglyceride Transfer Protein (MTTP), and β-oxidation, such as CPT2, but no differences in oxidative stress and inflammation, which were both increased similar to control mice [ 61 ], suggesting that hepatocytes alone are incapable of inducing inflammation. Interestingly, hepatocytes from mice with double liver-specific KO of c-met and Keap1 (in which Nrf2 is overactivated) and fed an MCD diet for 4 weeks, displayed increased liver mass but decreased triglyceride deposition [ 65 ].…”

Inflammation in Primary and Metastatic Liver Tumorigenesis–Under the Influence of Alcohol and High-Fat Diets

“…By inducing p62 at the transcriptional level, Nrf2 also establishes a positive feedback loop for its own activity [89]. Nrf2 has shown to be protective against the progression of NAFLD to NASH by ameliorating oxidative stress [90][91][92][93][94], although in the context of autophagy deficient mice, stabilization of Nrf2 by p62 sequestration led to increased liver injury [95]. Mutations in NFE2L2 (Nrf2) and KEAP1 that prevent Nrf2 degradation are two of the most frequently observed mutations in human HCC (3% and 5% of cases respectively), suggesting this pathway may be a driver of tumorigenesis in the liver [96].…”