Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion
Rashmi Chandra, … , Neil J. Freedman, Rodger A. Liddle
Rashmi Chandra, … , Neil J. Freedman, Rodger A. Liddle
Published July 25, 2013
Citation Information: J Clin Invest. 2013;123(8):3343-3352. https://doi.org/10.1172/JCI68587.
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Research Article Gastroenterology

Immunoglobulin-like domain containing receptor 1 mediates fat-stimulated cholecystokinin secretion

Abstract

Cholecystokinin (CCK) is a satiety hormone produced by discrete enteroendocrine cells scattered among absorptive cells of the small intestine. CCK is released into blood following a meal; however, the mechanisms inducing hormone secretion are largely unknown. Ingested fat is the major stimulant of CCK secretion. We recently identified a novel member of the lipoprotein remnant receptor family known as immunoglobulin-like domain containing receptor 1 (ILDR1) in intestinal CCK cells and postulated that this receptor conveyed the signal for fat-stimulated CCK secretion. In the intestine, ILDR1 is expressed exclusively in CCK cells. Orogastric administration of fatty acids elevated blood levels of CCK in wild-type mice but not Ildr1-deficient mice, although the CCK secretory response to trypsin inhibitor was retained. The uptake of fluorescently labeled lipoproteins in ILDR1-transfected CHO cells and release of CCK from isolated intestinal cells required a unique combination of fatty acid plus HDL. CCK secretion secondary to ILDR1 activation was associated with increased [Ca2+]i, consistent with regulated hormone release. These findings demonstrate that ILDR1 regulates CCK release through a mechanism dependent on fatty acids and lipoproteins and that absorbed fatty acids regulate gastrointestinal hormone secretion.

Authors

Rashmi Chandra, Yu Wang, Rafiq A. Shahid, Steven R. Vigna, Neil J. Freedman, Rodger A. Liddle

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Figure 3

Ildr1 gene deletion and CCK cell-specific expression.

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Ildr1 gene deletion and CCK cell-specific expression. (A) The mouse I...
(A) The mouse Ildr1 gene was disrupted by insertion of a β-Geo fusion reporter in intron 2, resulting in the production of β-galactosidase in targeted cells. The transmembrane domain is located in exon 4. A cysteine-rich region is present in exon 5 and a dileucine motif is located in exon 6 of human ILDR1. Introns are not drawn to scale. (B) Expression of EGFP and β-galactosidase in Ildr1–/– CCK-EGFP mouse duodenum was determined by immunostaining frozen sections with antibodies to EGFP (CCK cell reporter) and β-galactosidase (Ildr1–/– reporter). The left image shows colocalization (yellow) of EGFP (green) and β-galactosidase (red) antigens; nuclear staining (DAPI) is shown in blue (scale bar: 20 μm; original magnification, ×40). The top right images show staining of EGFP (green) or β-galactosidase (red) (scale bar: 5 μm). The bottom right image is a 3D reconstruction of this cell using Imaris software. The isosurface of the EGFP (green) cytoplasmic staining was rendered transparent to reveal β-galactosidase staining (red isosurface) and nucleus (blue isosurface) located within the cell (scale bar: 5 μm).