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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

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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 1

miR-153 is upregulated by HTG and aggravates AP.

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miR-153 is upregulated by HTG and aggravates AP.
(A) qPCR quantification...
(A) qPCR quantification of Mir153 level. Rnu6 was used as an endogenous control. (B) qPCR quantification of Mir153 level in the plasma of patients with AP. Ce_miR-39_1 was used as a spike in control. (C) Schematic of the experimental procedure to induce HTG-AP model in lentivirus-injected mice. (D) Representative images of H&E-stained pancreas and lung sections from HTG mice with cerulein-induced (top) or alcoholic (bottom) pancreatitis (n = 5–6 mice per group, scale bar: 200 μm). (E and F) Histological score of the pancreas and lung tissues from HTG mice with cerulein-induced (E) or alcoholic (F) pancreatitis scored by 2 pathologists independently (10 images per mouse). (G) mRNA level of Il1b in the pancreas from HTG mice with cerulein-induced or alcoholic pancreatitis. Gapdh was used as an endogenous control. (H) Serum IL-6 levels from HTG mice with cerulein-induced or alcoholic pancreatitis. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data are presented as mean ± SD and compared by 1-way ANOVA (A) or unpaired 2-tailed Student’s t test (B and E–H).
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