Cellular signalling · 2026
Membrane receptor TGR5 upregulates IP3R-induced calcium overload: Key mechanism of bile acid-induced acute pancreatitis.
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Zhong Zhi, Cheng Long, Jiang Zhiwei, Zhu Yongqiang, Zhao Chuan, Deng Chunlin, Yang Tingyu, Chen Maolin, Yu Qianjun, Xie Chuan, Dai Xin, Wang Tao
Аннотация
INTRODUCTION: Acute pancreatitis (AP) is a digestive system emergency with acomplex pathogenesis, with pathological calcium overload identified as a key driving factor. Excessive or improper exposure to bile acids (BAs) is the main pathogenic factor of AP, but the role of its membrane receptor TGR5 in AP and its downstream mechanisms has not been fully elucidated.
METHOD: A BAs-induced rat model of AP was established. The expression of TGR5 was detected. TGR5's role in AP was evaluated by knocking down TGR5. Pathological manifestations, serum indicators, inflammatory factor expression, oxidative stress levels, cell ultrastructure, and TGR5/IP3R expression were measured in each group. In vitro, AR42J cells received TGR5/IP3R intervention. Immunofluorescence, WB, and RT-qPCR were used to evaluate the roles and interrelationships of TGR5 and IP3R in AP. Calcium imaging technology was used to detect their effects on intracellular calcium ions.
RESULT: We found that TGR5 was widely expressed in pancreatic tissue. Its expression significantly increased in BAS-induced AP. In the AP rat model, knockdown of TGR5 can effectively alleviate pancreatic injury. It reduces serum enzymatic indicators and inflammatory factor levels, relieves oxidative stress, and improves mitochondrial structure. Cell experiments further confirmed that BAs can upregulate the expression of IP3R through TGR5. This upregulation causes intracellular calcium overload in acinar cells. Inhibiting or knocking down TGR5/IP3R expression and activity can play a protective role.
CONCLUSION: In conclusion, our research indicates that bile acids can trigger AP through the TGR5-IP3R‑calcium overload axis. Inhibiting TGR5/IP3R can alleviate calcium overload and exert a protective effect, providing new insights into the pathogenesis of AP.
METHOD: A BAs-induced rat model of AP was established. The expression of TGR5 was detected. TGR5's role in AP was evaluated by knocking down TGR5. Pathological manifestations, serum indicators, inflammatory factor expression, oxidative stress levels, cell ultrastructure, and TGR5/IP3R expression were measured in each group. In vitro, AR42J cells received TGR5/IP3R intervention. Immunofluorescence, WB, and RT-qPCR were used to evaluate the roles and interrelationships of TGR5 and IP3R in AP. Calcium imaging technology was used to detect their effects on intracellular calcium ions.
RESULT: We found that TGR5 was widely expressed in pancreatic tissue. Its expression significantly increased in BAS-induced AP. In the AP rat model, knockdown of TGR5 can effectively alleviate pancreatic injury. It reduces serum enzymatic indicators and inflammatory factor levels, relieves oxidative stress, and improves mitochondrial structure. Cell experiments further confirmed that BAs can upregulate the expression of IP3R through TGR5. This upregulation causes intracellular calcium overload in acinar cells. Inhibiting or knocking down TGR5/IP3R expression and activity can play a protective role.
CONCLUSION: In conclusion, our research indicates that bile acids can trigger AP through the TGR5-IP3R‑calcium overload axis. Inhibiting TGR5/IP3R can alleviate calcium overload and exert a protective effect, providing new insights into the pathogenesis of AP.