Fibroblast growth factor 21 alleviates acute pancreatitis via activation of the Sirt1-autophagy signalling pathway.

Qiongzhen Chen,Yali Zhang,Jinmeng Li,Xiaoning Yang,Xiaokun Li,Ming Ni,Junfeng Ma,Fanghua Gong,Zhuofeng Lin

doi:10.1111/jcmm.15190

Qiongzhen Chen, Yali Zhang + Show 7 more

Open Access

https://doi.org/10.1111/jcmm.15190

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Abstract

Fibroblast growth factor 21 (FGF21), a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity, alleviates the process of acute pancreatitis (AP). However, its mechanism remains elusive. The pathological and physiological characteristics of FGF21 are observed in both patients with AP and cerulein‐induced AP models, and the mechanisms of FGF21 in response to AP are investigated by evaluating the impact of autophagy in FGF21‐treated mice and cultured pancreatic cells. Circulating levels of FGF21 significantly increase in both AP patients and cerulein‐induced AP mice, which is accompanied by the change of pathology in pancreatic injury. Replenishment of FGF21 distinctly reverses cerulein‐induced pancreatic injury and improves cerulein‐induced autophagy damage in vivo and in vitro. Mechanically, FGF21 acts on pancreatic acinar cells to up‐regulate Sirtuin‐1 (Sirt1) expression, which in turn repairs impaired autophagy and removes damaged organs. In addition, blockage of Sirt1 accelerates cerulein‐induced pancreatic injury and weakens the regulative effect in FGF21‐activated autophagy in mice. These results showed that FGF21 protects against cerulein‐induced AP by activation of Sirtuin‐1‐autophagy axis.

Highlights

Acute pancreatitis (AP) is one of the most common acute abdomen diseases with a case fatality rate of 20%
We found that expression of Fibroblast growth factor 21 (FGF21) was up-regulated after the onset of AP
We found that FGF21 alleviated the pathological damage of AP by promoting expression of Sirt[1], repairing damaged mitochondria and lysosomes and alleviating autophagy abnormalities, thereby inhibiting abnormal expression of digestive enzymes and the inflammatory reaction (Figure S4)

Summary

| INTRODUCTION

Acute pancreatitis (AP) is one of the most common acute abdomen diseases with a case fatality rate of 20% It is primarily caused by excessive alcohol consumption, bile duct obstruction or drug allergy. Sirtuin-1 (Sirt1) is a representative member of the histone deacetylase family It reduces the activity of transcription factors and down-regulates inflammatory transcription genes by deacetylating histones, nuclear factor kappa B (NF-kB) and activator protein 1 (AP-1) in vivo.[19,20]. Sirt[1] plays an important role in the regulation of diabetic cardiomyopathy and lipid metabolism by FGF21.23,24 whether Sirt[1] mediates the protective effect of FGF21 in response to cerulein-induced AP keep further investigated. Our results demonstrate that FGF21 alleviates cerulein-induced AP by activation of Sirt1/autophagy signalling axis, which in turn repairs damaged mitochondria and lysosomes, inhibits the abnormal expression of prozymogen granules and inflammatory response and improves cerulein-induced acute pancreatic injury

| METHODS

Findings

| DISCUSSION