Inhibition of glycogen synthase kinase 3 β promotes autophagy to protect mice from acute liver failure mediated by peroxisome proliferator-activated receptor α

Our previous studies have demonstrated that inhibition of glycogen synthase kinase 3 β (GSK3 β ) activity protects mice from acute liver failure (ALF), whereas its protective and regulatory mechanism remains elusive. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that inhibition of GSK3 β mediates autophagy to inhibit liver inflammation and protect against ALF. In ALF mice model induced by d -galactosamine ( d -GalN) and lipopolysaccharide (LPS), autophagy was repressed compared with normal control, and d -GalN/LPS can directly induce autophagic flux in the progression of ALF mice. Autophagy activation by rapamycin protected against liver injury and its inhibition by 3-methyladenine (3-MA) or autophagy gene 7 (Atg7) small interfering RNA (siRNA) exacerbated liver injury. The protective effect of GSK3 β inhibition on ALF mice model depending on the induction of autophagy, because that inhibition of GSK3 β promoted autophagy in vitro and in vivo , and inhibition of autophagy reversed liver protection and inflammation of GSK3 β inhibition. Furthermore, inhibition of GSK3 β increased the expression of peroxisome proliferator-activated receptor α (PPAR α ), and the downregulated PPAR α by siRNA decreased autophagy induced by GSK3 β inhibition. More importantly, the expressions of autophagy-related gene and PPAR α are significantly downregulated and the activity of GSK3 β is significantly upregulated in liver of ALF patients with hepatitis B virus. Thus, we have demonstrated the new pathological mechanism of ALF that the increased GSK3 β activity suppresses autophagy to promote the occurrence and development of ALF by inhibiting PPAR α pathway.