Discoveries of GPR39 as an evolutionarily conserved receptor for bile acids and of its involvement in biliary acute pancreatitis

Sci Adv. 2024 Feb 2;10(5):eadj0146. doi: 10.1126/sciadv.adj0146.

Zhentao Zi ¹ ², Yi Rao ¹ ² ³

Affiliations

1 Chinese Institutes for Medical Research, Beijing (CIMR, Beijing) and the State Key Laboratory of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
2 Peking-Tsinghua Center for Life Sciences, PKU-IDG/McGovern Institute for Brain Research, School of Life Sciences, School of Pharmaceutical Sciences, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
3 Changping Laboratory, Chinese Institute of Brain Research Beijing and Research Unit of Medical Neurobiology, Chinese Academy of Medical Sciences, Beijing 102206, China.

PMID: 38306436 DOI: 10.1126/sciadv.adj0146

Abstract

Acute pancreatitis (AP) is one of the most common gastrointestinal diseases. Bile acids (BAs) were proposed to be a cause of AP nearly 170 years ago, though the underlying mechanisms remain unclear. Here, we report that two G protein-coupled receptors, GPR39 and GHSR, mediated cellular responses to BAs. Our results revealed GPR39 as an evolutionarily conserved receptor for BAs, particularly 3-O-sulfated lithocholic acids. In cultured cell lines, GPR39 is sufficient for BA-induced CA²⁺ elevation. In pancreatic acinar cells, GPR39 mediated BA-induced CA²⁺ elevation and necrosis. Furthermore, AP induced by BAs was significantly reduced in GPR39 knockout mice. Our findings provide in vitro and in vivo evidence demonstrating that GPR39 is necessary and sufficient to mediate BA signaling, highlighting its involvement in biliary AP pathogenesis, and suggesting it as a promising therapeutic target for biliary AP.

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