Activation of AMPK restored impaired autophagy and inhibited inflammation reaction by up-regulating SIRT1 in acute pancreatitis

Aims: Acute pancreatitis (AP) is a common inflammatory disorder with high incidence and mortality. AMPKSIRT1 pathway is involved in a variety of diseases, but its role in AP remains elusive. This study was aimed to explore the role of AMPK-SIRT1 pathway in AP. Main methods: AP models in vivo and vitro were constructed by intraperitoneal administration of L-arginine and caerulein-stimulated respectively. Rat serum amylase, IL-6 and TNF-alpha were determined by ELISA. The expression levels of AMPK, SIRT1, Beclin-1, LC3 and p62 were determined by qRT-PCR and western blot. The number of autophagosome was checked by transmission electron microscope. Key findings: Compared with NC rats, serum amylase, IL-6 and TNF-alpha were increased in AP rats. The expressions of AMPK and SIRT1 were decreased, while Beclin-1, LC3II/Iratio and p62 were markedly increased in AP rats. After activation of AMPK by metformin, expressions of p-AMPK alpha, SIRT1 were significantly raised, while expressions of Beclin-1, LC3 II/I, p62, TNF-alpha, IL-6 were reduced, and the number of autophagosome was decreased significantly in caerulein-stimulated AR42J cells. The inhibition of AMPK by compound C obtained opposite results. Significance: During AP occurrence, p-AMPK and SIRT1 were down-regulated, leading to the accumulation of p62, increase of autophagic vacuoles, damage of autophagy, and the occurrence of inflammation. It hinted that activation of AMPK restored impaired autophagy and inhibited inflammation reaction by up-regulating SIRT1. Our findings might provide important theoretical basis for explaining the pathogenesis of AP and investigating therapeutic target to treat and prevent AP.

Automated summary

In this study, the role of the AMPK-SIRT1 pathway in acute pancreatitis (AP) was investigated. The results showed that AMPK and SIRT1 were down-regulated in AP, leading to impaired autophagy and increased inflammation. Activation of AMPK restored impaired autophagy and inhibited inflammation by up-regulating SIRT1.