| Author |
Ren, F. Zhang, L. Zhang, X. Shi, H. Wen, T. Bai, L. Zheng, S. Chen, Y. Chen, D. Li, L. Duan, Z. |
| Description |
Country affiliation: China Author Affiliation: Ren F ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Zhang L ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Zhang X ( Department of Infectious Diseases, The Third Affiliated Hospital of Hebei Medical University, Shijiazhuang, China.); Shi H ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Wen T ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Bai L ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Zheng S ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Chen Y ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Chen D ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Li L ( Beijing Artificial Liver Treatment & Training Center, Beijing YouAn Hospital, Capital Medical University, Beijing, China.); Duan Z ( Department of Cell Biology, Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China.) |
| Abstract |
Our previous studies have demonstrated that inhibition of glycogen synthase kinase 3ß (GSK3ß) 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 GSK3ß 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 GSK3ß inhibition on ALF mice model depending on the induction of autophagy, because that inhibition of GSK3ß promoted autophagy in vitro and in vivo, and inhibition of autophagy reversed liver protection and inflammation of GSK3ß inhibition. Furthermore, inhibition of GSK3ß increased the expression of peroxisome proliferator-activated receptor (PPAR ), and the downregulated PPAR by siRNA decreased autophagy induced by GSK3ß inhibition. More importantly, the expressions of autophagy-related gene and PPAR are significantly downregulated and the activity of GSK3ß 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 GSK3ß activity suppresses autophagy to promote the occurrence and development of ALF by inhibiting PPAR pathway. |
