Dehydroepiandrosterone protects against hepatic glycolipid metabolic disorder and insulin resistance induced by high fat via activation of AMPK-PGC-1α-NRF-1 and IRS1-AKT-GLUT2 signaling pathways

Mitochondrial dysfunction, oxidative stress, or fatty liver are the key pathophysiological features for insulin resistance and obesity. Dehydroepiandrosterone (DHEA) can ameliorate obesity and insulin resistance; however, the mechanisms of these actions are poorly understood. The present study aimed to investigate the effect and possible mechanism of DHEA against glycolipid metabolic disorder and insulin resistance. Rats fed a high-fat diet (HFD) and palmitic acid (PA)-induced BRL-3A cells were employed to analyze the effect of DHEA on factors related to metabolic disorder and insulin resistance in vivo and in vitro. DHEA prevented lipid metabolism disorders by enhancing phospho (p)-protein kinase AMP-activated catalytic subunit alpha (AMPKα) (Thr172) protein level and its downstream lipid metabolism-related factors in liver of rats fed an HFD or in PA-induced BRL-3A cells. Meanwhile, DHEA ameliorated mitochondrial dysfunction through activation of the AMPK-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α)-nuclear respiratory factor-1 (NRF-1) pathway, which represented as the enhancing of the mtDNA copy number, ATP level, and membrane potential, and decreasing of reactive oxygen species production. Moreover, DHEA alleviated insulin resistance via increasing the phosphorylated insulin receptor substrate 1 (p-IRS1) (Tyr612) level and decreasing that of p-IRS1 (Ser307) level in liver of rats fed an HFD or in PA-induced BRL-3A cells, which subsequently enhanced p-protein kinase B (AKT) (Ser473) and membrane glucose transporter type 2 (GLUT2) expression levels. The protective effect of DHEA on high-fat-induced hepatic glycolipid metabolic disorder and insulin resistance are achieved through activation of the AMPK-PGC-1α-NRF-1 and IRS1-AKT-GLUT2 signaling pathways. The results provide compelling evidence for the mechanism by which DHEA prevents glycolipid metabolic disorder, and suggest its potential applications for controlling diabetes and obesity in animals and humans.