REGULATION OF MITOCHONDRIAL BIOGENESIS AND FUNCTION BY DSBA-L IN THE LIVER

Mitochondria in hepatocytes play a major role in maintaining whole-body energy metabolism and normalfunction of the liver. Impaired mitochondrial function is closely associated with various metabolic diseases suchas obesity, insulin resistance, and hepatosteatosis. However, the precise underlying mechanisms remain to befully elucidated. Filling this major gap of knowledge will yield new information on the mechanisms underlyingmitochondrial dysfunction-associated liver diseases, insulin resistance, and type 2 diabetes.Our current study focuses on the functional roles and mechanisms of action of the disulfide-bond-Aoxidoreductase-like protein (DsbA-L). We recently found that DsbA-L expression is significantly reduced in theliver of obese human subjects and diet-induced obese mice. In addition, loss- and gain-of-function studiesreveal that DsbA-L is a key regulator of mitochondrial integrity and function and its deficiency in the liver playsan important role in obesity-induced hepatosteatosis and metabolic dysfunction. In the current study, we will usemolecular and cellular approaches as well as knockout animal models to elucidate the mechanisms regulatingmitochondrial integrity and function under physiological and pathophysiological conditions. This research shouldshed new light on the link between obesity, mitochondrial impairment, and liver dysfunction and further ourunderstanding of the mechanisms underlying obesity-induced insulin resistance and metabolic diseases. Thus,our proposed studies should provide valuable information on the biology of DsbA-L potentially being useful astargets of anti-obesity and anti-insulin resistance therapeutics.