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Heat Shock Protein 72 Regulates Mitochondrial Integrity and Function in the Prevention of Hepatic Insulin Resistance

Nonalcoholic Fatty Liver Disease (NAFLD) encompasses a spectrum of disorders characterized by an accumulation of lipids in the liver, and is a significant risk factor for the development of insulin resistance and type 2 diabetes. Heat shock proteins (HSPs) can effectively prevent high fat diet‐induced glucose intolerance and skeletal muscle insulin resistance, improve oxidative capacity and increase mitochondrial function. The purpose of the current investigation was to determine whether HSP72, in particular, is protective against the development of hepatic triglyceride accumulation and insulin resistance. Male Wistar rats were fed a high‐fat diet (HFD) and received either weekly heat treatment (41°C for 20 min) or sham treatment (37°C for 20 min). In addition, primary hepatocytes were isolated from male C57BL/6 mice and subjected to either a single heat (42°C for 30 min) or sham (37°C for 30 min) treatment, transfected with HSP72 siRNA or exposed to insulin (60 μU/ml). Confocal microscopy images were obtained from cells incubated with tetramethylrhodamine (TMRE) and MitoTracker Green to assess mitochondria functionality. Weekly in vivo heat treatments reduced liver triglyceride accumulation, increased HSP72 levels, and modulated the protein levels of microtubule‐associated protein light chain 3 (LC3‐II) and p62 – two markers of autophagy. HSP72 siRNA in primary hepatocytes resulted in reduced mitochondrial function, reduced phosphorylation of AMP‐activated protein kinase (AMPK) and Akt, increased Parkin levels, and decreased LC3‐II levels. Our results indicate that weekly heat treatments protect against liver triglyceride accumulation in rats, and data from primary hepatocytes suggest a critical role for HSP72 in maintaining hepatic mitochondrial integrity and function. Our findings identify potential new HSP72‐mediated therapeutic targets for the regulation of hepatic mitophagy and prevention of metabolic disease.