Physcion alleviates chronic alcoholic hepatic inflammation and
pyroptosis through SIRT1-AMPK activation
Abstract
BACKGROUND AND PURPOSE Alcohol-associated liver disease (ALD) caused by
chronic alcohol consumption range from simple steatosis to alcoholic
hepatitis, fibrosis, and cirrhosis. Physcion is an anthraquinone
compound of Rheum palmatum L, a Chinese herbal medicine with possible
hepatoprotective properties. This study aimed to investigate the
protective effect and associated molecular mechanisms of physcion on
chronic alcoholic liver injury. EXPERIMENTAL APPROACH Chronic alcoholic
liver injury was induced by placing male C57BL/6 mice on Lieber-DeCarli
ethanol-containing diets for 10 days and then administering a single
dose of ethanol (5 g/kg body weight) via gavage. Human hepatic stellate
cells line, LX-2 cells were pretreated with physcion for 1 h prior to
ethanol stimulation. KEY RESULTS Physcion effectively ameliorated
ALD-induced serum aminotransferase and triglyceride levels, steatosis,
activated SIRT1-AMPK signaling, then inhibited hepatic NLRP3
inflammasome activation and GSDMD relevant in pyroptosis, the same as
the hepato-protection of AMPK and SIRT1 agonists. Physcion suppressed
ECM accumulation through inhibiting collagen-Ⅰ and α-SMA expression.
Moreover, physcion prevented the accumulation of HMGB1 and NF-κB p65
nuclear translocation and release. Importantly, silencing of SIRT1-AMPK
signaling eliminates the protective effect of physcion. CONCLUSIONS AND
IMPLICATIONS Activation of SIRT1-AMPK signaling is involved in ALD
pathogenesis, which alleviated by physcion through inhibiting NLRP3
inflammasome activation, inflammatory response and pyroptosis.
Therefore, manipulation of hepatic inflammation and pyroptosis through
strategies by targeting SIRT1-AMPK signaling holds great therapeutic
potential for ALD.