1557-P: Increased PAHSA Hydrolysis Driven by Mutant Carboxyl Ester Lipase (CEL) Contributes to Beta-Cell Dysfunction in MODY8

Maturity onset diabetes of the young type 8 (MODY8) is caused by genetic mutations in the CEL gene which is expressed primarily in pancreatic acinar cells. MODY8 patients develop pancreatic exocrine and endocrine dysfunction. How the enzymatic function of mutant (MUT) CEL contributes to the development of diabetes in MODY8 is unknown. Palmitic Acid Hydroxy Stearic Acids (PAHSAs) are signaling lipids that augment glucose-stimulated insulin secretion (GSIS). CEL is the major PAHSA hydrolytic enzyme in the pancreas. Aim: To determine whether CEL regulates insulin secretion and whether the increased PAHSA hydrolytic activity of MUT CEL contributes to MODY8 pathogenesis. Methods: We overexpressed wildtype (WT) or MUT CEL in acinar cells in vitro and in vivo. In vivo, we used 2 approaches both with AAV8 driven by an acinar cell specific promoter: intraductal AAV injections in wildtype mice and intraperitoneal AAV injections in CEL KO mice. CEL overexpression was detected exclusively in acinar cells. Results: 9-PAHSA augments GSIS in human pancreatic beta cells. Recombinant CEL inhibits the PAHSA effect. MUT CEL overexpression in acinar cells increases 9-PAHSA hydrolytic activity compared to WT CEL. In vivo, MUT CEL expression in acinar cells of wildtype mice markedly impairs glucose tolerance. In CEL KO mice, expression of MUT CEL in acinar cells impairs GSIS. Both WT and MUT CEL reduce total pancreatic PAHSA levels in CEL KO mice. However, 12/13-PAHSAs were reduced only with MUT CEL expression. Conclusions: 1) CEL in acinar cells alters PAHSA hydrolysis and modulates insulin secretion. 2) MUT CEL potentially contributes to the development of diabetes by increasing PAHSA hydrolysis and thereby limiting the normal PAHSA-induced augmentation of GSIS. 3) These data highlight the critical role of acinar-beta cell interactions and the physiologic role of PAHSAs in insulin secretion and provide opportunities for developing strategies to treat MODY8 and other forms of diabetes. Disclosure A. Santoro: None. S. Kahraman: Employee; Boehringer-Ingelheim. G. Basile: None. K. El Jellas: None. J. Hu: None. R. Tarpey: None. B.B. Johansson: None. E. Dirice: None. I. Syed: None. D. Siegel: None. A. Molven: None. B.B. Kahn: Advisory Panel; Janssen Pharmaceuticals, Inc. Consultant; Vida Ventures Advisors, Arrowhead Pharmaceuticals, Inc. R. Kulkarni: Advisory Panel; Novo Nordisk, Biomea Fusion, Inc. Consultant; Inversago Pharma. Advisory Panel; REDD Pharmaceutical. Funding K01 DK128075 (Anna Santoro), U01DK135095 (Rohit N. Kulkarni), R01DK067536 (Rohit N. Kulkarni), NIH R01 DK106210 (Barbara B. Kahn), JPB foundation (Barbara B. Kahn), and NIH P30 DK135043 (Barbara B. Kahn). Anna Santoro, Sevim Kahraman, Barbara B. Kahn and Rohit N. Kulkarni contributed equally.