PLX111046

GSE102982: JNK activation of BIM promotes hepatic oxidative stress, steatosis and insulin resistance in obesity

• Organsim mouse
• Type RNASEQ
• Target gene
• Project ARCHS4

The BCL-2 family are crucial regulators of the mitochondrial pathway of apoptosis in normal physiology and disease. Besides their role in cell death, BCL-2 proteins have been implicated in the regulation of mitochondrial oxidative phosphorylation and cellular metabolism. However, it remains unclear whether these proteins have a physiological role in glucose homeostasis and metabolism in vivo. Here we report that fat accumulation in the liver increases JNK-dependent BIM expression in hepatocytes. We generated liver-specific BIM knockout (BLKO) mice to determine the consequences of hepatic BIM deficiency in diet-induced obesity. BLKO mice had lower hepatic lipid content, increased insulin signalling and improved global glucose metabolism. Consistent with this, lipogenic and lipid uptake genes were downregulated and lipid oxidation enhanced in obese BLKO mice. Moreover, oxidative stress, oxidation of protein tyrosine phosphatases and activation of PPAR-g/STAT1/CD36 were decreased in livers/hepatocytes from BLKO mice, suggesting a mechanism for their metabolic phenotype. Importantly, adenovirus-mediated knockdown of BIM reduced fat accumulation and improved insulin sensitivity in high fat fed mice. Our data postulate BIM as a novel therapeutic target regulating mitochondrial bioenergetics and liver function in obesity. SOURCE: Esteban,N,Gurzov (egurzov@svi.edu.au) - St Vincent’s Institute of Medical Research