Dehydroepiandrosterone protects against oleic acid-triggered mitochondrial dysfunction to relieve oxidative stress and inflammation via activation of the AMPK-Nrf2 axis by targeting GPR30 in hepatocytes

Fatty liver hemorrhage syndrome (FLHS) seriously threatens the health and performance of laying hens, and the occurrence and development of FLHS are closely related to oxidative damage and inflammation; thus, diets supple-mental with activated substances to relive the oxidative stress and inflammation maybe effectively control the oc-currences of FLHS. Dehydroepiandrosterone (DHEA) has beneficial effects in fat-reduction, anti-oxidation and anti -inflammation, and it was widely applied to alleviate multiple metabolic-related diseases; however, there are few re-ports on whether DHEA can prevent against metabolic-related diseases by modulating oxidative stress and inflam-mation, especially FLHS in laying hens. Herein, present study aimed to investigate the regulatory actions and potential molecular mechanism of DHEA on inflammation and oxidative stress triggered by oleic acid (OA)-stimulation in primary chicken hepatocytes and chicken hepatocellular carcinoma cell line (LMH). The results showed that DHEA significantly alleviated oxidative stress challenged by OA-stimulation via activation of AMP-activated protein kinase (AMPK)-nuclear factor-erythroid 2-related factor 2 (Nrf2) signaling pathway in hepatocytes, which led to relieving effect of DHEA on inflammatory by inhibiting mitogen-activated protein kinases (MAPKs) and nuclear factor kappa B (NF-kappa B) signaling pathways. Mechanistically, we found that the activation of AMPK-Nrf2 signaling pathway by DHEA treatment was mediated by G-protein coupled estrogen receptor (GPR30/GPER) in OA-stimulated hepatocytes. Further investigation found that DHEA activated the GPR30-mediated AMPK-Nrf2 signaling pathways to increase antioxidant capacity and inhibit mitochondrial reactive oxygen species (ROS) overproduction, which thereby inhib-iting the activation of ROS-induced MAPK and NF-kappa B signaling pathways in OA-stimulated hepatocytes. Overall, these data demonstrated that DHEA attenuates the oxidative stress and inflammation triggered by OA-stimulation, and these beneficial effects of DHEA are achieved by activating the GPR30-mediated AMPK-Nrf2 signaling to prevent the impairment of mitochondrial function, and thereby inhibiting the activation of ROS-induced MAPK and NF-kappa B signaling pathways in hepatocytes. These results revealed the effects and mechanisms of DHEA on oxidative stress and inflammation, and also provide substantial information to support it as a potential nutritional supplement in pre-venting the occurrences of FLHS in laying hens and other metabolic-related diseases in animals and humans.

Automated summary

Fatty liver hemorrhage syndrome (FLHS) seriously affects the health and performance of laying hens and is closely associated with oxidative stress and inflammation. This study explores the potential of Dehydroepiandrosterone (DHEA) to mitigate FLHS by modulating oxidative stress and inflammation in chicken hepatocytes. The results demonstrate that DHEA activates the AMPK-Nrf2 signaling pathway, effectively reducing oxidative stress and inflammation in hepatocytes stimulated by oleic acid (OA). These findings highlight the beneficial effects and mechanisms of DHEA in preventing FLHS and other metabolic-related diseases in animals and humans.