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

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.