Saikosaponin D attenuates metabolic associated fatty liver disease by coordinately tuning PPARα and INSIG/SREBP1c pathway

Metabolic associated fatty liver disease (MAFLD) is a progressive chronic liver disease, yet there is still a lack of effective pharmacological therapies at present. Saikosaponin D (SSd) has been reported to exhibit hepatoprotective and anti-steatosis activities in our previous research.The current study aims to further investigate the underlying mechanisms of SSd on MAFLD from the perspectives of the crosstalk between fatty acid (FA) biosynthesis and catabolism to provide strong support for further clinical management of MAFLD.A MAFLD mouse model induced by a high-fat diet and glucose-fructose water (HFSW) was used for in vivo study. HepG2 cells, primary mouse hepatocytes and adipocytes were further employed for in vitro studies.SSd improved intracellular lipid accumulation both in the liver and adipose tissues in HFSW-fed mice. Mechanistically, SSd may serve as a potent PPARα agonist, and the activation of PPARα by SSd in both hepatocytes and adipocytes not only promoted FA oxidation but also concurrently induced INSIG1/2 expression, which subsequently inhibited SREBP1c maturation and ultimately FA synthesis. Moreover, the regulative effect of SSd on lipid metabolism was abolished by the PPARα inhibitor, GW6471.This study demonstrated that SSd improved lipid homeostasis by coordinately regulating PPARα activation-mediated both inhibition of SREBP1c-dependent FA biosynthesis and induction of FA degradation, and thus shed novel light on the discovery of SSd-based therapeutic strategies for MAFLD.