Unlocking the potential of atractylenolide II: Mitigating non-alcoholic fatty liver disease through farnesoid X receptor-endoplasmic reticulum stress interplay

Evidences indicate that farnesoid X receptor (FXR) activation mitigates non-alcoholic fatty liver disease (NAFLD) by reducing endoplasmic reticulum (ER) stress. However, the mechanisms underlying FXR-ER stress interactions in combating NAFLD remain obscure. Moreover, few phytochemicals have been noted to improve NAFLD through this pathway. Here, we found that FXR activation directly induces the transcription of sarco/endoplasmic reticulum Ca²⁺ ATPase 2 (SERCA2), which acts as an ER stress repressor. This process leads to the dephosphorylation of the eukaryotic translation initiation factor 2 subunit α (eIF2α) within hepatocytes, consequently alleviating ER stress. Furthermore, through drug binding assays, luciferase reporter gene testing, gene expression analysis and biochemical evaluation, we identified the phytochemical atractylenolide II (AT-II) as a novel FXR agonist that effectively triggers SERCA2 activation. Our results showed AT-II effectively supresses accumulation of lipids and ER stress in palmitic acid-induced hepatocytes. In <i>in vivo</i> experiments, we demonstrated that AT-II attenuates fatty liver in diet- or chemical-induced NAFLD mouse models. Additionally, we showed that AT-II corrects diet-induced obesity, serum dyslipidemia, metabolic complications, and insulin resistance. Mechanistically, AT-II reduces ER stress, lipogenesis and inflammation and improves hepatic insulin signaling through stimulation of the hepatic FXR-SERCA2-eIF2α axis in mice. This conclusion was further reinforced by <i>Serca2</i> knockdown both <i>in vivo</i> and <i>in vitro</i>, as well as FXR silencing in hepatocytes. Our findings provide new insights into the FXR-ER stress interplay in the control of NAFLD and suggest the potential of AT-II as an FXR agonist for the treatment of NAFLD through SERCA2 activation.