A Major Lineage of Enteroendocrine Cells Coexpress CCK, Secretin, GIP, GLP-1, PYY, and Neurotensin but Not Somatostatin

被引：254

作者：

Egerod, Kristoffer L. ^{[2
]}

Engelstoft, Maja S. ^{[2
]}

Grunddal, Kaare V. ^{[2
]}

Nohr, Mark K. ^{[2
]}

Secher, Anna ^{[4
]}

Sakata, Ichiro ^{[5
]}

Pedersen, Jens ^{[3
,6
]}

Windelov, Johanne A. ^{[3
,6
]}

Fuchtbauer, Ernst-Martin ^{[9
]}

Olsen, Jorgen ^{[7
]}

Sundler, Frank ^{[10
]}

Christensen, Jan P. ^{[8
]}

Wierup, Nils ^{[10
]}

Olsen, Jesper V. ^{[4
]}

Holst, Jens J. ^{[3
,6
]}

Zigman, Jeffrey M. ^{[5
]}

Poulsen, Steen S. ^{[3
,6
]}

Schwartz, Thue W. ^{[1
,2
]}

机构：

[1] Univ Copenhagen, Panum Inst, Mol Pharmacol Lab, Dept Neurosci & Pharmacol,Fac Hlth Sci, DK-2200 Copenhagen, Denmark

[2] Univ Copenhagen, Fac Hlth Sci, Novo Nordisk Fdn Ctr Basic Metab Res, Sect Metab Receptol & Enteroendocrinol, DK-2200 Copenhagen, Denmark

[3] Univ Copenhagen, Fac Hlth Sci, Sect Translat Physiol, DK-2200 Copenhagen, Denmark

[4] Univ Copenhagen, Novo Nordisk Fdn Ctr Prot Res, Dept Prote, Fac Hlth Sci, DK-2200 Copenhagen, Denmark

[5] Univ Texas SW Med Ctr Dallas, Div Hypothalam Res, Dept Internal Med, Dallas, TX 75390 USA

[6] Univ Copenhagen, Dept Biomed Sci, DK-2200 Copenhagen, Denmark

[7] Univ Copenhagen, Dept Cellular & Mol Med, DK-2200 Copenhagen, Denmark

[8] Univ Copenhagen, Dept Int Hlth Immunol & Microbiol, DK-2200 Copenhagen, Denmark

[9] Univ Aarhus, Dept Mol Biol, DK-2200 Copenhagen, Denmark

[10] Lund Univ, Ctr Diabet, Dept Clin Sci Malmo, S-20502 Malmo, Sweden

来源：

ENDOCRINOLOGY | 2012年 / 153卷 / 12期

关键词：

SMALL-INTESTINE; GASTROINTESTINAL-TRACT; TARGETED ABLATION; ENDOCRINE CELL; STEM-CELLS; DIFFERENTIATION; GUT; CHOLECYSTOKININ; EXPRESSION; PATHWAYS;

D O I：

10.1210/en.2012-1595

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Enteroendocrine cells such as duodenal cholecystokinin (CCK cells) are generally thought to be confined to certain segments of the gastrointestinal (GI) tract and to store and release peptides derived from only a single peptide precursor. In the current study, however, transgenic mice expressing enhanced green fluorescent protein (eGFP) under the control of the CCK promoter demonstrated a distribution pattern of CCK-eGFP positive cells that extended throughout the intestine. Quantitative PCR and liquid chromatography-mass spectrometry proteomic analyses of isolated, FACS-purified CCK-eGFP-positive cells demonstrated expression of not only CCK but also glucagon-like peptide 1 (GLP-1), gastric inhibitory peptide (GIP), peptide YY (PYY), neurotensin, and secretin, but not somatostatin. Immunohistochemistry confirmed this expression pattern. The broad coexpression phenomenon was observed both in crypts and villi as demonstrated by immunohistochemistry and FACS analysis of separated cell populations. Single-cell quantitative PCR indicated that approximately half of the duodenal CCK-eGFP cells express one peptide precursor in addition to CCK, whereas an additional smaller fraction expresses two peptide precursors in addition to CCK. The coexpression pattern was further confirmed through a cell ablation study based on expression of the human diphtheria toxin receptor under the control of the proglucagon promoter, in which activation of the receptor resulted in a marked reduction not only in GLP-1 cells, but also PYY, neurotensin, GIP, CCK, and secretin cells, whereas somatostatin cells were spared. Key elements of the coexpression pattern were confirmed by immunohistochemical double staining in human small intestine. It is concluded that a lineage of mature enteroendocrine cells have the ability to coexpress members of a group of functionally related peptides: CCK, secretin, GIP, GLP-1, PYY, and neurotensin, suggesting a potential therapeutic target for the treatment and prevention of diabetes and obesity. (Endocrinology 153: 5782-5795, 2012)

引用

页码：5782 / 5795

页数：14

共 45 条

[1] IMMUNOHISTOCHEMICAL STUDIES INDICATE MULTIPLE ENTEROENDOCRINE CELL-DIFFERENTIATION PATHWAYS IN THE MOUSE PROXIMAL SMALL-INTESTINE [J].