Molecular mechanisms of lipid sensing in human cholecystokinin-secreting enteroendocrine cells.

Authors

Marta Santos-Hernández, Mae Tabbada, Nademah Tamkin, Linxia Li, Nunzio Guccio, Adam Davison, Chris A Smith, Richard Kay, Constanza Alcaino, Mirza Baig, Austin Punnoose, Yining Xu, Rula Bany Bakar, Frank Reimann, Fiona M Gribble

Published in

Molecular metabolism. Pages 102448. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

Cholecystokinin (CCK) has been implicated in coordinating lipid digestion and satiety. However, the molecular mechanisms underlying nutrient-dependent CCK-release from human I-cells are not well understood, at least in part due to the cells' scattered distribution and a lack of reliable CCK-assays. Here we used human intestinal organoids to characterize lipid-sensing mechanisms underlying CCK release.
Human duodenal organoids were genetically engineered using CRISPR-Cas9 to insert either the fluorescent protein Venus or the cAMP reporter Epac-S-H187 at the CCK locus. Transcriptomic profiling of CCK-positive and negative cells was performed following fluorescent-activated cell sorting. Intracellular calcium and cAMP as well as CCK-GRAB-sensor secretory responses were assessed during live-cell imaging, and CCK secretion was quantified by LC-MS/MS. To evaluate lipid-sensing pathways, FFAR1, FFAR4, and GPR119 knockout organoids were generated.
Transcriptomic analysis identified expression of lipid-sensing GPCRs in I-cells, including FFAR1, FFAR4, FFAR2, GPR119, GPBAR1, OR51E1 and OR51E2. Fatty acids and FFAR1 agonists increased intracellular calcium, whereas agonists of GPBAR1 and GPR119, and short-chain fatty acids elevated cAMP. CCK release was triggered by FFAR1, GPBAR and GPR119 agonists, and fatty acids with chain-length > C₈. FFAR1 knockout organoids exhibited impaired Ca²⁺ and CCK secretory responses to fatty acids, whereas responses of FFAR4 KO organoids were like wild-type.
In human I-cells, FFAR1 plays a crucial role in lipid-induced CCK release, whereas FFAR4 appears to be redundant in this context. These findings improve understanding of human CCK physiology and identify potential therapeutic targets for metabolic regulation and appetite control.

PMID:
42805486
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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