Exercise attenuates hepatic ectopic lipid deposition in high fat-diet rats via PKA-mediated phosphorylation of Perilipin5

The lipid droplet-associated protein Perilipin5 exerts a dual regulatory function in hepatic lipid accumulation and lipolysis, positioning it as a critical target for non-alcoholic fatty liver disease (NAFLD) therapeutics. Given the well-established benefits of exercise in mitigating NAFLD, elucidating the role of Perilipin5 in this process is essential for understanding exercise-induced metabolic adaptations Twenty-four SD rats were randomly assigned to standard diet, high-fat diet, or high-fat diet plus treadmill exercise groups for six weeks. Assessments included body weight, blood glucose, serum lipid profiles, liver histology, hepatic lipid content, and biomarkers of liver injury. Additionally, lipolytic protein expression and the co-localization of Perilipin5 and CGI-58 were analyzed. Results revealed that six weeks of treadmill exercise attenuated high-fat diet-induced weight gain, glucose intolerance, and ameliorated insulin sensitivity and dysregulated lipid metabolism, leading to a reduced NAFLD activity score (NAS) and preventing hepatic ectopic lipid deposition and liver injury. Notably, hepatic Perilipin5 protein levels remained largely unchanged under both high-fat diet and exercise conditions; however, its function was modulated through post-translational modifications. Exercise promoted PKA-mediated Perilipin5 phosphorylation, whereas a high-fat diet significantly suppressed this phosphorylation. As a result, exercise diminished Perilipin5-CGI-58 interaction while enhancing ATGL activity. Therefore, regular exercise effectively reduced hepatic triglyceride accumulation and alleviated NAFLD in high-fat diet-fed rats, likely by promoting PKA-mediated Perilipin5 phosphorylation, thereby releasing CGI-58 and ultimately enhancing hepatic lipolysis.