Abstract
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 β-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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anticholesteremic Agents / pharmacology
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
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Bile Acids and Salts / metabolism
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Blood Glucose / metabolism
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Colesevelam Hydrochloride / pharmacology
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Colon / cytology
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Colon / metabolism
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Diet, High-Fat
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Enteroendocrine Cells / metabolism*
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Glucagon-Like Peptide 1 / genetics*
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Glucagon-Like Peptide 1 / metabolism
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Glycolysis
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Humans
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Ileum / cytology
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Ileum / metabolism
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Insulin / metabolism
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Insulin Secretion
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Insulin-Secreting Cells / metabolism
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Intestinal Mucosa / metabolism*
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Intestines / cytology
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Jejunum / cytology
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Jejunum / metabolism
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Mice
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Mice, Knockout
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Mice, Obese
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Nuclear Proteins / metabolism
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Obesity / genetics
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Obesity / metabolism
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Proglucagon / drug effects
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Proglucagon / genetics
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Proglucagon / metabolism
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RNA, Messenger / metabolism*
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Receptors, Cytoplasmic and Nuclear / genetics*
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Receptors, G-Protein-Coupled / genetics
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Sequestering Agents / pharmacology
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Signal Transduction
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Transcription Factors / metabolism
Substances
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Anticholesteremic Agents
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Bile Acids and Salts
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Blood Glucose
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Gpbar1 protein, mouse
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Insulin
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MLXIPL protein, human
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Mlxipl protein, mouse
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Nuclear Proteins
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RNA, Messenger
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Receptors, Cytoplasmic and Nuclear
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Receptors, G-Protein-Coupled
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Sequestering Agents
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Transcription Factors
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farnesoid X-activated receptor
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Proglucagon
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Glucagon-Like Peptide 1
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Colesevelam Hydrochloride