Mitochondria in hepatocytes play a major role in maintaining whole-body energy metabolism and normal function of the liver. Impaired mitochondrial function is closely associated with various metabolic diseases such as obesity, insulin resistance, and hepatosteatosis. However, the precise underlying mechanisms remain to be fully elucidated. Filling this major gap of knowledge will yield new information on the mechanisms underlying mitochondrial 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-A oxidoreductase-like protein (DsbA-L). We recently found that DsbA-L expression is significantly reduced in the liver of obese human subjects and diet-induced obese mice. In addition, loss- and gain-of-function studies reveal that DsbA-L is a key regulator of mitochondrial integrity and function and its deficiency in the liver plays an important role in obesity-induced hepatosteatosis and metabolic dysfunction. In the current study, we will use molecular and cellular approaches as well as knockout animal models to elucidate the mechanisms regulating mitochondrial integrity and function under physiological and pathophysiological conditions. This research should shed new light on the link between obesity, mitochondrial impairment, and liver dysfunction and further our understanding 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 as targets of anti-obesity and anti-insulin resistance therapeutics.
Obesity has been well documented as an important factor leading to fatty liver, insulin resistance, and type 2 diabetes, but the underlying mechanisms remain elusive. The proposed study is to characterize key regulators of mitochondrial DNA biogenesis and function and determine whether and how mitochondrial dysfunction contributes obesity- induced hepatosteatosis and liver disorder. Results from this study may lead to the development of new therapeutic strategies to prevent obesity and its associated metabolic diseases.