REGULATION OF INTESTINAL ACE2 EXPRESSION BY THE BILE ACID RECEPTOR GPBAR1 IS MEDIATED BY A GPBAR1/GLP-1/GLP-1R AXIS

ABSTRACT

Background: ACE2 is a carboxypeptidase homolog to the dipeptidase ACE but with different substrate specificity;while ACE principally acts as a carboxydipeptidase (peptidyldipeptidase) removing the C-terminal dipeptide from Ang I to form Ang II, ACE2 functions exclusively as a carboxypeptidase removing a single C-terminal amino acid from Ang II generating Ang- (1-7) or, much less efficiently, from Ang I forming Ang-(1-9). ACE and ACE2 than playing a key role in regulating the renin–angiotensin–aldosterone system (RAAS). In the normal lung, ACE2 mRNA is mainly expressed by type II alveolar epithelial cells and endothelial cells, but the level of expression increases in response to inflammation while is downregulated in response to SARS-CoV infection. ACE2, mRNA and protein, is highly expressed in the gastrointestinal tract, with the higher expression detected in epithelial cells of the ileum and the colon where mediates the absorption of amino acids. ACE2 expression in the intestine undergoes regulation in response to a variety of factors including intestinal microbiota and inflammation. Furthermore, previous studies have suggested that insulinotropic factor glucagon like peptide (GLP)-1 might regulate ACE2 expression in the heart, suggesting a potential interaction of GLP1 with ACE2. GPBAR1, G Protein Bile Acid Receptor, is robustly expressed in the gastrointestinal tract and its activation in the intestine promotes the release of GLP-1. Aim: to investigate the possible interaction between bile acids via GPBAR1 and the expression of ACE2 in the gastrointestinal tract. Materials and Methods: HT29 cells treated with TNF-α + IL-1β and mouse models of colitis were used to assess ACE2 expression and treatment with BAR501, a GPBAR1 agonist, was used to investigate its modulation. Results: The inflammatory stimulus increased the expression of Ace2 in HT29 cells and in colon of mice according to the data obtained in human samples from patient with IBD. GPBAR1 agonism by BAR501 relieved inflammation both in vitro and in vivo but in vitro this effect induced down-regulation of ACE2 while in vivo administration of BAR501 increased ACE2 expression. In mouse model of colitis, inflammation up-regulated also the GLP-1 gene expression that was further increased by BAR501 and instead, the administration of Exendina- 3, a GLP-1R antagonist was able to block the up-regulation of Ace2 expression exerted by BAR501. Conclusions: In conclusion, our results demonstrate that both in vivo and in vitro activation of GPBAR1 by a selective agonist exerts an anti-inflammatory effect. On the other hand, in vivo activation of GPBAR1 in the colon induces the release of GLP-1, which mediates some of the anti-inflammatory effects exerted by the receptor, and induces further upregulation of Ace2 by GPBAR1/GLP-1/GLP-1R axis.(Figure Presented)