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.
Highlights
Formation of reactive oxygen species (ROS) has been considered classically a pathophysiological phenomenon critically involved in the progression from simple hepatic steatosis to steatohepatitis
It is well established that stabilization and activation of Nrf2 through pharmacological or genetic targeting improves cellular redox homeostasis and survival through transcriptional upregulation of antioxidant and detoxifying genes [8]. In line with these studies, we recently showed that activation of Nrf2 in hepatocytes afforded by genetic deletion of Keap1 was able to reduce triglycerides accumulation and ROS generation in mice subjected to experimental models of NASH [9]
Deletion of the exon 15 in c-metΔhepa mice operated by the crerecombinase under control of the albumin promoter resulted in a defective intracellular activation of the receptor as indicated by impaired phosphorylation of specific tyrosine residues
Summary
Formation of reactive oxygen species (ROS) has been considered classically a pathophysiological phenomenon critically involved in the progression from simple hepatic steatosis to steatohepatitis. Cellular compartments responsible for lipid catabolism such as mitochondria and lysosomes increase their activity with a consequent generation of free radicals that trigger molecular signals leading to cell death and release of proinflammatory mediators. In this context, the use of antioxidant buffering against the generation of ROS has been shown to partially reduce the progression of nonalcoholic steatohepatitis. Data concerning the consequences of HGF stimulation on the cellular generation of free radicals are still quite controversial. Whereas in primary cell lines and tissues such as cardiomyocytes [1] and neurons [2], stimulation with HGF was shown
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