AI Article Synopsis
- - The study investigates the role of the antioxidant transcription factor Nrf2 in mice lacking the Keap1 gene, focusing on how this affects liver metabolism and progression from simple fat accumulation to more severe liver disease (NASH) in response to high-fat diets.
- - Results showed that Keap1 knockout mice had significantly lower lipid droplet content and triglyceride levels in their livers compared to control mice, indicating reduced fat storage due to enhanced fat breakdown processes.
- - While the absence of Keap1 lowered liver fat accumulation and reduced cell death caused by a specific diet, it did not affect inflammation levels or the activation of certain pro-fibrotic genes, suggesting that Nrf2's protective effects mainly target fat metabolism
Article Abstract
Generation of reactive oxygen species (ROS) in response to fatty acids accumulation has been classically proposed as a possible "second hit" triggering progression from simple steatosis to non-alcoholic steatohepatitis (NASH). In this study we challenged hepatocyte-specific Keap1 knockout mice (Keap1(Δhepa)) and littermate Cre- controls (Keap1(fx/fx)) with two different diet models of NASH in order to evaluate the effects of the anti-oxidant transcription factor Nrf2 over-activation on hepatic metabolism and disease progression. After 4 weeks of MCD diet the liver/body weight ratio of Keap1(Δhepa) mice was significantly higher compared to littermate controls with no differences in total body weight. Strikingly, liver histology revealed a dramatic reduction of lipid droplets confirmed by a decreased content of intra-hepatic triglycerides in Keap1(Δhepa) compared to controls. In parallel to reduced expression of genes involved in lipid droplet formation, protein expression of Liver X Receptor (LXRα/β) and Peroxisome proliferator-activated receptor α (PPARα) was significantly decreased. In contrast, genes involved in mitochondrial lipid catabolism were markedly up-regulated in Keap1(Δhepa) livers. A similar phenotype characterized by inhibition of lipogenesis in favor of increased mitochondrial catabolic activity was also observed after 13 weeks of western diet administration. MCD-induced apoptosis was significantly dampened in Keap1(Δhepa) compared to Keap1(fx/fx) as detected by TUNEL, cleaved caspase-3 and Bcl-2 protein expression analyses. However, no differences in inflammatory F4/80- and CD11b-positive cells and pro-fibrogenic genes were detected between the two groups. Although hepatic lack of Keap1 did not ameliorate inflammation, the resulting constitutive Nrf2 over-activation in hepatocytes strongly reduced hepatic steatosis via enhanced lipid catabolism and repressed de novo lipogenesis during murine NASH development.
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| http://dx.doi.org/10.1016/j.freeradbiomed.2015.12.014 | DOI Listing |
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