Heat Shock Protein 72 Regulation of Metabolism

Abstract

The prevalence of metabolic disease continues to rise in the United States, leading to conditions such as metabolic syndrome, diabetes, and NAFLD. Heat shock proteins (HSPs) are molecular chaperones which aid in protein folding during cellular stress. These proteins are also important in metabolic function, through inhibiting inflammation and increasing oxidative capacity in skeletal muscle. Reduced HSPs may also lead to metabolic disease, demonstrated by reduced HSP72 expression in skeletal muscle of diabetic patients and in the liver with the progression of NAFLD. Our studies further demonstrate that disruption in the HSP response could be an underlying commonality in various metabolic conditions and tissues. First, we found that a reduction in HSPs in skeletal muscle of a post-menopausal rat model is associated with reduced mitochondrial protein expression, increased lipid storage, and reduced exercise capacity. We also investigated the role of HSP72 in the liver. A loss of HSP72 in hepatocytes led to a reduction in fatty acid oxidation, mitochondrial dysfunction, and increased lipid storage. A reduction in HSPs in both the skeletal muscle and the liver may increase susceptibility to the development of metabolic disease. Our work also demonstrates that activation of HSPs has potential to protect from metabolic dysfunction. We found that a heat treatment intervention increases HSP72 in the liver, reduces hepatic triglyceride storage, and improves whole-body glucose homeostasis in rodents fed a high-fat diet. We also found that acute and chronic exercise increase HSP72 protein expression in the liver. The induction of HSPs with exercise was associated with changes in autophagy and mitophagy protein expression, which may protect hepatocytes from accumulation of damaged organelles. This work strongly suggests that HSP72 maintains whole-body metabolic homeostasis through protecting against lipid accumulation in both skeletal muscle and liver. Therapies which activate HSP72 may be the key to protecting against metabolic disease.