ATF4-mediated histone deacetylase HDAC1 promotes the progression of acute pancreatitis

Xiaofeng Deng,Xiongying Miao,Yu He,Bo Yu

doi:10.1038/s41419-020-03296-x

Abstract

Acute pancreatitis (AP), an acute inflammatory process, can be difficult to diagnose. Activating transcription factor 4 (ATF4) has been reported to participate in the pathogenesis of AP. Additionally, histone deacetylases (HDACs) are shown to be closely related to the development of a variety of diseases, including inflammation disease. In our study, we tried to highlight the role of ATF4 in AP through regulation of HDAC1. Firstly, we validated the effect of ATF4 on pancreatic acinar cell proliferation, apoptosis, and inflammation through in vitro experiments on cellular models of caerulein-induced AP. Next, we examined the correlation between ATF4 and HDAC1, and between HDAC1 with neutral endopeptidase (NEP) and kruppel-like factor 4 (KLF4). Finally, the regulatory role of ATF4 in AP was further assessed by determination of pathological conditions, biochemical indicators and inflammation through in vivo experiments on caerulein-induced AP mouse models. After AP induction, highly expressed ATF4 was observed, and silencing ATF4 could promote pancreatic acinar cell proliferation and inhibit apoptosis. ATF4 could bind to the HDAC1 promoter and upregulate its expression in AP. Moreover, HDAC1 could increase KLF4 expression by inhibiting NEP expression. Functionally, silencing ATF4 could suppress AP through regulation of NEP-mediated KLF4 via downregulation of HDAC1. Above all, our study uncovered the promotive role of ATF4 in AP through upregulation of HDAC1.

Highlights

Acute pancreatitis (AP), an inflammatory disease, is the main cause of hospitalization for gastrointestinal disorders in the United States and many other countries[1].The rising incidence of this disease might further augment the frequency of disorders in several systems long after clinical treatment of pancreatitis[2]
The expressions of Activating transcription factor 4 (ATF4) and histone deacetylase 1 (HDAC1) in each group were detected by western blot analysis, and the results showed that silenced sh-ATF4 treatment led to reduced expressions of ATF4 and HDAC1 while there was no significant difference in ATF4 expression but increased HDAC1 after oe-HDAC1 treatment (Fig. 4A)
kruppel-like factor 4 (KLF4) in each group were detected by western blot analysis, and the results showed that sh-ATF4 treatment led to increased neutral endopeptidase (NEP) expression but decreased ATF4, HDAC1, and KLF4 while there was no significant change in ATF4, HDAC1, and NEP but increased KLF4 after oeKLF4 treatment (Fig. 7A)

Summary

Introduction

Acute pancreatitis (AP), an inflammatory disease, is the main cause of hospitalization for gastrointestinal disorders in the United States and many other countries[1]. The rising incidence of this disease might further augment the frequency of disorders in several systems (such as endocrine, exocrine, and aberrant bone metabolism) long after clinical treatment of pancreatitis[2]. Several promising strategies have emerged as novel therapeutic options for the early management of AP, such as the application of enteral nutrition and antibiotics, haemofiltration and protease inhibitors[3]. The pancreatic acinar cells are a crucial cell source for the synthesis, delivery, Department of General Surgery, the Second Xiangya Hospital of Central South.

Methods

Results

Conclusion