GLP-1 Mediates Regulation of Colonic ACE2 Expression by the Bile Acid Receptor GPBAR1 in Inflammation

Abstract

Background & Aims: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. Methods: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn’s disease (CD) patients and three mouse models of colitis and Gpbar1−/− mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. Results: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. Conclusions: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α- and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2.

Modulatory Roles of AHR, FFAR2, FXR, and TGR5 Gene Expression in Metabolic-Associated Fatty Liver Disease and COVID-19 Outcomes

“…Similarly, BA regulation of ACE2 via GPBAR1 has also been documented. A study by Biagioli et al (2022) showed that in vivo activation of GPBAR1 increased the production of glucagon-like peptide-1 (GLP-1) in intestinal L cells, which in turn promoted colonic cell expression of ACE2 [51]. These findings suggest that the potential protective effects of bile acid receptors in patients with COVID-19 may be mediated through the modulation of ACE2 expression alongside influencing the immune response.…”

Modulatory Roles of AHR, FFAR2, FXR, and TGR5 Gene Expression in MAFLD and COVID-19 Outcomes

“…Similarly, BA regulation of ACE2 via GPBAR1 has also been documented. A study by Biagioli et al (2022) showed that in vivo activation of GPBAR1 increased the production of glucagon-like peptide-1 (GLP-1) in intestinal L cells, which in turn promoted colonic cell expression of ACE2 [44]. These findings suggest that the potential protective effects of bile acid receptors in COVID-19 patients may be mediated through modulation of ACE2 expression alongside influencing the immune response.…”