Arjunolic acid from Cyclocarya paliurus as a pleiotropic phytochemical effectively counteracts the "multiple parallel...

Arjunolic acid (AA), a bioactive triterpenoid isolated from Cyclocarya paliurus, could protect against NAFLD in our previous experiment. Based on the well-established "multiple parallel hits" hypothesis of NAFLD, we herein comprehensively assessed whether AA can serve as a pleiotropic phytochemical to show the ameliorative effects on NAFLD. Our results showed that AA treatment significantly mitigated high-fat diet (HFD)-induced systemic symptoms of NAFLD, including obesity (0.45-fold vs. HFD for body weights, P < 0.01), dyslipidemia (0.70-fold vs. HFD for serum TC, P < 0.01; 0.69-fold vs. HFD for serum TG, P < 0.01; 0.59-fold vs. HFD for serum LDL-c, P < 0.01; 1.37-fold vs. HFD for serum HDL-c, P < 0.01; 0.52-fold vs. HFD for serum FFA, P < 0.01), and insulin resistance. Additionally, AA further protected against the intrahepatic "hits" including hepatic steatosis, oxidative stress and inflammation (0.61-fold vs. HFD for liver IL-6, P < 0.01; 0.60-fold vs. HFD for liver IL-1β, P < 0.01; 0.59-fold vs. HFD for liver TNF-α, P < 0.01), adipose tissue-liver and gut-liver axis disturbances in NAFLD mice. Mechanism research found that AA could indirectly activate Sirt1/AMPK-modulated lipid metabolism through restoring the NAD⁺ pool, and induce autophagy in the liver. These findings indicate AA exerts pleiotropic protection against NAFLD, partly via Sirt1/AMPK activation and autophagy induction.