Dysregulated SREBP1c/miR-153 signaling induced by hypertriglyceridemia worsens acute pancreatitis and delays tissue repair

Juanjuan Dai,Bin Hu,Guoyong Hu,Jiyao Xu,Zengkai Wu,Li Wen,Xiao Han,Yan He,Shuangjun Shen,Yingchun Ren,Yangyang Hu,Bin Li,Mingjie Jiang,Jingbo Xiao,Xingpeng Wang

doi:10.1172/jci.insight.138584

Abstract

Severe acute pancreatitis (AP) is a life-threatening disease with up to 30% mortality. Therefore, prevention of AP aggravation and promotion of pancreatic regeneration are critical during the course and treatment of AP. Hypertriglyceridemia (HTG) is an established aggravating factor for AP that hinders pancreatic regeneration; however, its exact mechanism remains unclear. Using miRNA sequencing and further verification, we found that miRNA-153 (miR-153) was upregulated in the pancreas of HTG animal models and in the plasma of patients with HTG-AP. Increased miR-153 aggravated HTG-AP and delayed pancreatic repair via targeting TRAF3. Furthermore, miR-153 was transcriptionally suppressed by sterol regulatory element-binding transcription factor 1c (SREBP1c), which was suppressed by lipoprotein lipase malfunction-induced HTG. Overexpressing SREBP1c suppressed miR-153 expression, alleviated the severity of AP, and facilitated tissue regeneration in vivo. Finally, therapeutic administration of insulin also protected against HTG-AP via upregulating SREBP1c. Collectively, our results not only provide evidence that HTG leads to the development of more severe AP and hinders pancreatic regeneration via inducing persistent dysregulation of SREBP1c/miR-153 signaling, but also demonstrate that SREBP1c activators, including insulin, might be used to treat HTG-AP in patients.

Highlights

Acute pancreatitis (AP) is a common and potentially life-threatening inflammatory disorder of the exocrine pancreas
Since the crucial roles of miRNAs have been implicated in various pathological processes, including pancreatitis [26], we performed miRNA sequencing in the pancreas of cerulein-induced AP mice, with or without 4 weeks of administration of P-407
We found that TRAF3 expression was downregulated by either direct lentiviral-based miR-153 overexpression or HTG-induced miR-153 overexpression in vivo, which could be restored in HTG with miR-153 inhibition, both during the acute phase (Figure 3B and Supplemental Figure 6, A and B) and the pancreatic regeneration phase (Figure 3C)

Summary

Introduction

Acute pancreatitis (AP) is a common and potentially life-threatening inflammatory disorder of the exocrine pancreas. As an established aggravating factor for AP, hypertriglyceridemia (HTG) is the third most common cause of AP in the United States and the second most common cause of AP in China [2]. Patients with severe and very severe HTG are prone to develop more severe AP [3, 4]. Severe and very severe HTG delays pancreatic recovery after AP [5] and increases the risk of developing recurrent and chronic pancreatitis [6, 7], which altogether can lead to other sequelae, including pancreatic exocrine insufficiency [8]. Effective drugs for treating HTG-AP are not yet readily available

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Results

Conclusion