CTRP3 ameliorates cerulein-induced severe acute pancreatitis in mice via SIRT1/NF-κB/p53 axis

Abstract

Severe acute pancreatitis (SAP) is a common and life-threatening clinical acute abdominal disease. C1q/tumor necrosis factor-related protein 3 (CTRP3), a novel paralog of adiponectin, has been identified as a crucial regulator in multiple types of inflammatory disorders. However, the biological role of CTRP3 in SAP remains poorly understood. This study aimed to characterize the role of CTRP3 in SAP and illuminate the potential mechanisms involved. In the current study, SAP mouse models were induced by seven hourly intraperitoneal injection of cerulein (50 μg/kg) and an immediate intraperitoneal injection of lipopolysaccharide (10 mg/kg) after the last cerulein administration. Histological examination and serological analysis demonstrated that SAP mouse models were successfully established. Herein, we found that CTRP3 expression was significantly decreased in the pancreatic tissues of SAP mice compared with normal control mice. Furthermore, we explored the effects of CTRP3 rescue in SAP mice and discovered that CTRP3 over-expression attenuated pathological lesions, inhibited inflammatory mediator release and repressed acinar cell apoptosis. Notably, mechanistic studies revealed that CTRP3 over-expression suppressed NF-κB p65 phosphorylation and p53 acetylation to alleviate cerulein-induced SAP in mouse models through activation of silent information regulator 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent protein deacetylase. Collectively, our data indicate that CTRP3 may exert its protective effects in SAP mice via regulation of SIRT1-mediated NF-κB and p53 signaling pathways, implying a promising therapeutic strategy against SAP.

The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation

“…We have already shown that CTRP3 ameliorates development of autoimmune arthritis (21). Furthermore, CTRP3 is implicated in the regulation of myocardiac dysfunction, inflammatory bowel disease, severe acute pancreatitis and chronic kidney diseases (21)(22)(23)(24)(25). Because involvement of Th17 cells is suggested in these diseases (72)(73)(74)(75), it is possible that CTRP3 regulates excess inflammation in these diseases.…”

“…CTRP3 is implicated in the development of myocardiac dysfunction, inflammatory bowel diseases, severe acute pancreatitis and chronic kidney diseases (22)(23)(24)(25). CTRP3 also functions as an antagonist for LPS, and modulates antiinflammatory functions of monocytes, macrophages, adipocytes and fibroblasts (26)(27)(28)(29)(30)(31).…”

AMPK-SIRT1 Pathway Modulates The Apoptosis, Proliferation and Migration of AR42J Cells By Regulating p53 and NF-κB

“…Furthermore, it has been reported that p53 acetylation could be capable of suppressing cell proliferation and survival, which would contribute to development of AP [29] . Related research has suggested that the activation of SIRT1 could inhibit the acetylation of p53 and repress the apoptosis of acinar cells, thus to alleviate the SAP model induced by caerulein [30] . In addition, another study indicated that resveratrol (SIRT1 activator) signi cantly reduced the severity of AP, effectively improved the survival rate, relieved the in ammatory response and decreased the acinar necrosis and apoptosis in a mouse model of L-arginine-induced acute necrotizing pancreatitis, which might be related to the enhancement of SIRT1-mediated deacetylation of p53 [27] .…”

Drug discovery and formulation development for acute pancreatitis

“…demonstrated that the receptor-interacting protein kinase 1(RIPK1)/NF-κB/aquaporin 8 (AQP8) axis might serve as a potential regulatory pathway to inhibit acinar cell necrosis in early acute pancreatitis (Duan et al., 2019 ). The latest study proved that C1q/tumor necrosis factor-related protein 3 (CTRP3) exerted protective effects in acute pancreatitis via suppressing silent information regulator 1 (SIRT1)/NF-κB/p53 axis (Lv et al., 2020 ).…”