Dysregulated SREBP1c/miR-153 signaling induced by hypertriglyceridemia worsens acute pancreatitis and delays tissue repair
Juanjuan Dai, … , Xingpeng Wang, Guoyong Hu
Juanjuan Dai, … , Xingpeng Wang, Guoyong Hu
Published January 25, 2021
Citation Information: JCI Insight. 2021;6(2):e138584. https://doi.org/10.1172/jci.insight.138584.
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Research Article Gastroenterology Therapeutics

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

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.

Authors

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

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Figure 3

miR-153 promotes inflammatory responses and ADM formation via targeting TRAF3.

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miR-153 promotes inflammatory responses and ADM formation via targeting ...
(A) Relative luciferase activity of the luciferase reporter assay. Plasmids carrying the TRAF3 3’-UTR and its wild type (WT) or mutant (MT) counterpart of predicted miR-153 binding site were cotransfected with miR-153-3p mimic or its control to NIH3T3, luciferase activity was measured 48 hours later. (B) Representative Western blots showing the expression of TRAF3 and its downstream p38 MAPK/JNK signaling in AP tissues of indicated mice (n = 6–8 mice per group). (C) qPCR quantification showing relative expression of Traf3 in the pancreas of indicated mice at days 2 and 5 after cerulein stimulation. Gapdh was used as an endogenous control. (D) LDH activity in the supernatant of primary acinar cells, an LDH leakage positive control was used to determine percentage of LDH leakage. (E) PI uptake by primary acinar cells were measured, total cell counts in each well was determined after Triton X-100 treatment. (F) Representative Western blots showing protein level of TRAF3, total and phosphorylated p38, JNK, and p65, in isolated primary acinar cells from 3 independent experiments. (G) Relative mRNA level of Tnf, Il1b, and Il6 in isolated primary acinar cells. Gapdh was used as an endogenous control. (H) Statistical analysis of ductal-like structures at day 4 in 3D culture of primary acinar cells (10 images per group). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data are presented as mean ± SD and compared by unpaired 2-tailed Student’s t test (A) or 1-way ANOVA (C–E, G, and H).