Cucurbitacin B ameliorates AKT-driven fatty liver disease in mice by suppressing AKT/mTORC1 and LXRα/SREBP1 lipogenic pathways

Dysregulated de novo lipogenesis (DNL) is an essential characteristic of nonalcoholic fatty liver disease (NAFLD). Cucurbitacin B (CuB) is a triterpenoid found in the edible plants of Cucurbitaceae with a broad spectrum of beneficial effects. Here, we investigate the in vivo anti-steatotic efficacy of CuB in an AKT-driven NAFLD mouse model established using hydrodynamic injection. Hepatocyte lines with artificial activation of AKT were used for in vitro experiments. The results demonstrate that CuB effectively attenuates the content of triglyceride and total cholesterol (P < 0.05) and hepatocyte injury (P < 0.01) in the AKT-injected mice. Mechanically, CuB directly represses AKT/mTORC1 and LXRα/SREBP1 signaling, leading to the downregulation of key lipogenic enzymes, acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN) in vivo and in vitro. Taken together, CuB attenuates AKT-driven hepatic steatosis by retarding DNL, indicating that CuB may be beneficial for the treatment of NAFLD, especially in the subset displaying activated AKT/mTORC1 and lipogenic cascades.