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Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells

Trabelsi, M. S. (author)
Daoudi, M. (author)
Prawitt, J. (author)
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Ducastel, S. (author)
Touche, V. (author)
Sayin, Sama I. (author)
Gothenburg University,Göteborgs universitet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberglaboratoriet,Institute of Medicine, Department of Molecular and Clinical Medicine,Wallenberg Laboratory
Perino, A. (author)
Brighton, C. A. (author)
Sebti, Y. (author)
Kluza, J. (author)
Briand, O. (author)
Dehondt, H. (author)
Vallez, E. (author)
Dorchies, E. (author)
Baud, G. (author)
Spinelli, V. (author)
Hennuyer, N. (author)
Caron, S. (author)
Bantubungi, K. (author)
Caiazzo, R. (author)
Reimann, F. (author)
Marchetti, P. (author)
Lefebvre, P. (author)
Bäckhed, Fredrik, 1973 (author)
Gothenburg University,Göteborgs universitet,Wallenberglaboratoriet,Institutionen för medicin, avdelningen för molekylär och klinisk medicin,Wallenberg Laboratory,Institute of Medicine, Department of Molecular and Clinical Medicine
Gribble, F. M. (author)
Schoonjans, K. (author)
Pattou, F. (author)
Tailleux, A. (author)
Staels, B. (author)
Lestavel, S. (author)
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 (creator_code:org_t)
2015-07-02
2015
English.
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • Bile acids are signalling molecules, which activate the transmembrane receptor TGR5 and the nuclear receptor FXR. BA sequestrants (BAS) complex bile acids in the intestinal lumen and decrease intestinal FXR activity. The BAS-BA complex also induces glucagon-like peptide-1 (GLP-1) production by L cells which potentiates beta-cell glucose-induced insulin secretion. Whether FXR is expressed in L cells and controls GLP-1 production is unknown. Here, we show that FXR activation in L cells decreases proglucagon expression by interfering with the glucose-responsive factor Carbohydrate-Responsive Element Binding Protein (ChREBP) and GLP-1 secretion by inhibiting glycolysis. In vivo, FXR deficiency increases GLP-1 gene expression and secretion in response to glucose hence improving glucose metabolism. Moreover, treatment of ob/ob mice with the BAS colesevelam increases intestinal proglucagon gene expression and improves glycaemia in a FXR-dependent manner. These findings identify the FXR/GLP-1 pathway as a new mechanism of BA control of glucose metabolism and a pharmacological target for type 2 diabetes.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Keyword

TYPE-2 DIABETES-MELLITUS
BILE-ACID RECEPTORS
RAT SMALL-INTESTINE
GLUCOSE-HOMEOSTASIS
GLP-1 SECRETION
METABOLIC-RATE
FXR
MICE
OBESITY
EXPRESSION
Multidisciplinary Sciences

Publication and Content Type

ref (subject category)
art (subject category)

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