3 years ago

JNK Activation of BIM Promotes Hepatic Oxidative Stress, Steatosis and Insulin Resistance in Obesity.

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. It remains unclear, however, 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. To determine the consequences of hepatic BIM deficiency in diet-induced obesity, we generated liver-specific BIM knockout (BLKO) mice. BLKO mice had lower hepatic lipid content, increased insulin signalling and improved global glucose metabolism. Consistent with these findings, lipogenic and lipid uptake genes were downregulated and lipid oxidation enhanced in obese BLKO mice. Mechanistically, BIM deficiency improved mitochondrial function and decreased oxidative stress, oxidation of protein tyrosine phosphatases and ameliorated activation of PPAR-γ/SREBP1/CD36 in hepatocytes from high fat fed mice. Importantly, short-term knockdown of BIM rescued obese mice from insulin resistance, evidenced by reduced fat accumulation and improved insulin sensitivity. Our data indicate that BIM is an important regulator of liver dysfunction in obesity, and a novel therapeutic target for restoring hepatocyte function.

Publisher URL: http://doi.org/10.2337/db17-0348

DOI: 10.2337/db17-0348

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