Abstract
AimThe pathogenesis of non-alcoholic fatty liver disease is currently unclear, however, lipid accumulation leading to endoplasmic reticulum stress appears to be pivotal in the process. At present, FOXO1 is known to be involved in NAFLD progression. The relationship between necroptosis and non-alcoholic steatohepatitis has been of great research interest more recently. However, whether FOXO1 regulates ER stress and necroptosis in mice fed with a high fat diet is not clear. Therefore, in this study we analyzed the relationship between non-alcoholic steatohepatitis, ER stress, and necroptosis.Main MethodsMale C57BL/6J mice were fed with an HFD for 14 weeks to induce non-alcoholic steatohepatitis. ER stress and activation of necroptosis in AML12 cells were evaluated after inhibition of FOXO1 in AML12 cells. In addition, mice were fed with AS1842856 for 14 weeks. Liver function and lipid accumulation were measured, and further, ER stress and necroptosis were evaluated by Western Blot and Transmission Electron Microscopy.Key FindingsMice fed with a high fat diet showed high levels of FOXO1, accompanying activation of endoplasmic reticulum stress and necroptosis. Further, sustained PA stimulation caused ER stress and necroptosis in AML12 cells. At the same time, protein levels of FOXO1 increased significantly. Inhibition of FOXO1 with AS1842856 alleviated ER stress and necroptosis. Additionally, treatment of mice with a FOXO1 inhibitor ameliorated liver function after they were fed with a high fat diet, displaying better liver condition and lighter necroptosis.SignificanceInhibition of FOXO1 attenuates ER stress and necroptosis in a mouse model of non-alcoholic steatohepatitis.
Highlights
Obesity and its related metabolic syndrome have gradually become an important factor affecting human health all over the world
We investigated the impact of palmitic acid (PA) on ER stress, a cellular response that is closely related to altered metabolism in nonalcoholic fatty liver disease (NAFLD), in AML12 cells
We found that protein expression of receptorinteracting protein1 (RIP1), Receptor-interacting protein3 (RIP3) and phosphorylated mixed lineage kinase domain-like protein (MLKL) was strongly increased in the treatment group when compared with the control group
Summary
Obesity and its related metabolic syndrome have gradually become an important factor affecting human health all over the world. NAFLD is characterized by excessive fat deposition in hepatocytes caused by other definite liver-damaging factors besides alcohol and can progress to non-alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma (Qian et al, 2019). The treatment of NAFLD is a focus of world health concerns. The treatment of NAFLD is mainly based on diet control and exercise. Medical treatment of non-alcoholic steatohepatitis lacks the effects of properly designed drugs and equipment (Brunt et al, 2015), in part because, at present, the mechanism of non-alcoholic fatty liver disease is not completely clear. The first hit is insulin resistance caused by fat accumulation, and the second hit is lipid peroxidation, oxidative stress, and secondary inflammation. Oxidative stress, including mitochondrial dysfunction and ER stress, is the main cause of cell injury and death in the disease
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