Hormonal
Activation of the nuclear receptor FXR in enteroendocrine L-cells inhibits GLP-1 production by suppressing glycolysis and proglucagon transcription, whereas FXR deactivation (via deficiency or bile acid sequestrants) increases GLP-1 and improves glucose tolerance.
This research highlights that the specific bile acid receptor targeted matters for glucose control. While TGR5 agonists increase GLP-1, FXR activation suppresses it. Therefore, therapies aiming to boost GLP-1 (like bile acid sequestrants) work partly by deactivating FXR, not just by activating TGR5. This suggests that optimal treatments might combine TGR5 activation with FXR inhibition to maximize GLP-1 production.
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.
Why this rating
Strong evidence from multiple models (in vitro, ex vivo human biopsies, and multiple mouse genotypes) with consistent mechanistic findings.
Source
Farnesoid X receptor inhibits glucagon-like peptide-1 production by enteroendocrine L cells
Mohamed Trabelsi et al. · Nature Communications · 2015
DOI 10.1038/ncomms8629
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