PFKFB3 controls acinar IP3R-mediated Ca2+ overload to regulate acute pancreatitis severity
Tan Zhang, Shengchuan Chen, Liang Li, Yuepeng Jin, Siying Liu, Zhu Liu, Fengyu Shi, Lifen Xie, Panpan Guo, Andrew C. Cannon, Akmal Ergashev, Haiping Yao, Chaohao Huang, Baofu Zhang, Lijun Wu, Hongwei Sun, Siming Chen, Yunfeng Shan, Zhengping Yu, Ezequiel J. Tolosa, Jianghuai Liu, Martin E. Fernandez-Zapico, Feng Ma, Gang Chen
Tan Zhang, Shengchuan Chen, Liang Li, Yuepeng Jin, Siying Liu, Zhu Liu, Fengyu Shi, Lifen Xie, Panpan Guo, Andrew C. Cannon, Akmal Ergashev, Haiping Yao, Chaohao Huang, Baofu Zhang, Lijun Wu, Hongwei Sun, Siming Chen, Yunfeng Shan, Zhengping Yu, Ezequiel J. Tolosa, Jianghuai Liu, Martin E. Fernandez-Zapico, Feng Ma, Gang Chen
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Research Article Inflammation Metabolism

PFKFB3 controls acinar IP3R-mediated Ca2+ overload to regulate acute pancreatitis severity

Abstract

Acute pancreatitis (AP) is among the most common hospital gastrointestinal diagnoses; understanding the mechanisms underlying the severity of AP is critical for development of new treatment options for this disease. Here, we evaluate the biological function of phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) in AP pathogenesis in 2 independent genetically engineered mouse models of AP. PFKFB3 was elevated in AP and severe AP (SAP), and KO of Pfkfb3 abrogated the severity of alcoholic SAP (FAEE-SAP). Using a combination of genetic, pharmacological, and molecular studies, we defined the interaction of PFKFB3 with inositol 1,4,5-trisphosphate receptor (IP3R) as a key event mediating this phenomenon. Further analysis demonstrated that the interaction between PFKFB3 and IP3R promotes FAEE-SAP severity by altering intracellular calcium homeostasis in acinar cells. Together, our results support a PFKFB3-driven mechanism controlling AP pathobiology and define this enzyme as a therapeutic target to ameliorate the severity of this condition.

Authors

Tan Zhang, Shengchuan Chen, Liang Li, Yuepeng Jin, Siying Liu, Zhu Liu, Fengyu Shi, Lifen Xie, Panpan Guo, Andrew C. Cannon, Akmal Ergashev, Haiping Yao, Chaohao Huang, Baofu Zhang, Lijun Wu, Hongwei Sun, Siming Chen, Yunfeng Shan, Zhengping Yu, Ezequiel J. Tolosa, Jianghuai Liu, Martin E. Fernandez-Zapico, Feng Ma, Gang Chen

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Figure 5

PFKFB3 is involved in the regulation of pathological calcium overload in acinar cells.

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PFKFB3 is involved in the regulation of pathological calcium overload in...
(A and B) KEGG pathway enrichment (A) and GO analysis (B) in pancreas from cKO and WT mice from the FAEE-SAP model. (C) The enrichment plot comparing the transcriptome of cKO mice and WT mice in FAEE-SAP from GSEA analysis. Normalized Enrichment Score (NES), –2.133; normal P value, 0.001. (D) Heatmap shows the core enrichment genes in the pathway named response to calcium ion. (E and F) Representative traces of POA (E) or POAEE (F) induced Ca2+ elevations. The representative images are the first and last frames of pancreas prestained with Fluo-4. Scale bar: 40 μm. KAN0438757 (25 mg/kg) was administered by i.p. injection 1 hour prior to detection; DMSO in saline solution was used as a control. P values calculated using unpaired Student’s t test. *P < 0.05, **P < 0.01, ***P < 0.001. Data are shown as mean ± SD. Each experiment was performed at least in triplicate.