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Kay Macleod, PhD

Mitochondrial pathways in hepatic insulin resistance and disease.

The proper functioning of mitchondria and control of overall mitochondrial mass are critically tied up with healthy metabolism, not surprisingly given that the mitochondria are the site of oxidative phosphorylation, Krebs cycle and fatty acid oxidation. Consistently, genetic mutations or drug treatments that affect mitochondrial function are increasingly being shown to also modulate obesity, insulin resistance and fatty liver disease. As part of our on-going studies to explore the significance of mitochondrial integrity and autophagy in metabolism, we have identified a novel role for BNIP3 in regulating the switch from glucose storage/fatty acid synthesis in the fed state, to suppression of these pathways and increased glucose output from the liver during fasting. We propose that BNip3 achieves this, either indirectly through effects on mitochondrial integrity or directly through a novel metabolic function at the mitochondria, for example through control of substrate flux. Finally, and most importantly, we have shown that BNip3 protein is induced in the liver by fasting and down-regulated by high fat diet and thus have proposed that the BNIP3-mediated metabolic switch in the liver is regulated by insulin signaling. This work has relevance for understanding how hepatic insulin resistance develops during the progression of Type 2 diabetes, and suggests that the ability to modulate BNip3 levels and/or activity could be useful in the treatment of disease.