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

2017; American Diabetes Association; Volume: 66; Issue: 12 Linguagem: Inglês

10.2337/db17-0348

1939-327X

Sara A. Litwak, Lokman Pang, Sandra Galić, Mariana Igoillo‐Esteve, William J. Stanley, Jean-Valéry Turatsinze, Kim Loh, Helen E. Thomas, Arpeeta Sharma, Eric Trépo, Christophe Moreno, Daniel J. Gough, Décio L. Eizirik, Judy B. de Haan, Esteban N. Gurzov,

Peroxisome Proliferator-Activated Receptors

The members of 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. In this study, we report that fat accumulation in the liver increases c-Jun N-terminal kinase–dependent BCL-2 interacting mediator of cell death (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 signaling, 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 and oxidation of protein tyrosine phosphatases, and ameliorated activation of peroxisome proliferator–activated receptor γ/sterol regulatory element-binding protein 1/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.