Carboxyl ester lipase truncation mutant unveils lipotoxicity induced pancreatic β-cell demise
- Biochem Biophys Res Commun. 2025 Oct 17:789:152800. doi: 10.1016/j.bbrc.2025.152800.
- 1. Department of Endocrinology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian, 350001, China.
- 2. Integrated Clinical Medicine Program, College of Basic Medical Sciences, Harbin Medical University, Harbin, 150076, Heilongjiang, China.
- 3. Department of Endocrinology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, Fuzhou, Fujian, 350001, China. Electronic address: [email protected].
Mutations in carboxyl ester Lipase (CEL) cause maturity-onset diabetes of the young type 8 (MODY8), yet the mechanism linking exocrine CEL deficiency to β-cell failure remains unclear. Here, we demonstrate that a truncating CEL mutant (MUT-CEL, c.538 + 16C > T) is aberrantly internalized by β-cells, where it forms cytotoxic aggregates that resist degradation. These aggregates induce endoplasmic reticulum stress, trigger a sustained unfolded protein response, and drive β-cells into a senescent state characterized by cell cycle arrest and loss of identity markers. Crucially, we identify cyclin-dependent kinase 4 (CDK4) dysfunction as a central mediator of this lipotoxicity induced senescence. Restoration of CDK4 activity rescues β-cell proliferation and function in vitro and in vivo, revealing a targetable pathway to mitigate β-cell demise in MODY8.