Protective Properties of FOXO1 Inhibition in a Murine Model of Non-alcoholic Fatty Liver Disease Are Associated With Attenuation of ER Stress and Necroptosis

Abstract

The 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 Methods: Male 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.

Peripherally Selective CB1 Receptor Antagonist Improves Symptoms of Metabolic Syndrome in Mice

“…Blockade of FOXO1 has been shown to reduce phenotypes of NAFLD and NASH, including endoplasmic reticulum stress, ALT, AST, triglycerides, and body weight. 38 An impact on FOXO1 phosphorylation has previously been demonstrated after treatment with a CB1R inverse agonist in a DIO mouse model, 39 and our results expand on additional impacts of CB1R activity on Foxo1 gene expression level. Therefore, CB1R antagonism appears to reduce de novo lipogenesis associated genes and this observation provides a mechanistic rationale for the development of this class of compounds for liver diseases.…”

“…We additionally observed significant impacts on expression of genes that drive steatosis, Foxo1 and Pparg . Blockade of FOXO1 has been shown to reduce phenotypes of NAFLD and NASH, including endoplasmic reticulum stress, ALT, AST, triglycerides, and body weight . An impact on FOXO1 phosphorylation has previously been demonstrated after treatment with a CB1R inverse agonist in a DIO mouse model, and our results expand on additional impacts of CB1R activity on Foxo1 gene expression level.…”

Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice

“…A previous study showed that Foxo1 OE resulted in TG accumulation 32 . Furthermore, the expression of Foxo1 is upregulated in the liver of humans and mice with NAFLD 33 , 34 . Based on these observations, we determined whether Kindlin-2 modulates Foxo1 expression in hepatocytes.…”

Targeting programmed cell death in metabolic dysfunction-associated fatty liver disease (MAFLD): a promising new therapy

“…The destruction of membrane integrity during necroptosis releases various proinflammatory mediators and promotes the progression of MAFLD [ 53 ]. Ding et al found that AS1842856 improves MAFLD by inhibiting forkhead box protein O1 (FOXO1), ERS and necroptosis [ 54 ]. TNF-α-mediated necroptosis is widely recognized as the most classical pathway.…”