Forkhead box transcription factors are required for expression of the glycemia‐protective enzyme angiotensin‐converting enzyme 2 in pancreatic β‐cells (1108.10)

Angiotensin‐converting enzyme 2 (ACE2) opposes Ang‐II signaling and improves β‐cell function in several diabetic animal models. We previously reported that diabetes progression reduces islet ACE2 expression and that HNF1α dose‐dependently increases ACE2 expression in pancreatic islets. Because HNF1α is not sufficient for the full ACE2 expression, we hypothesized that ACE2 expression in β‐cells is regulated by other factors binding to evolutionarily conserved motifs of the human ACE2 promoter. A putative motif for forkhead box transcription factors is located 144‐153 bases upstream of the translational start site. Mutation of the motif in luciferase reporters decreased ACE2 promoter activity in 832/13 insulinoma cells by 56% (p<0.001). Overexpression of FOXO1 slightly increased (< 3‐fold) promoter activity and led to FOXO1 binding to the motif as observed by EMSA. However, the endogenous complexes in 832/13 cells binding to the motif contained FOXA proteins with the most abundant of these complexes containing FOXA1/2. Furthermore, ENCODE data suggest that an additional FOXA1/2 binding site is located further upstream in the ACE2 promoter. We conclude that forkhead box transcription factors, in particular of the FOXA class, are required for expression of ACE2 in β‐cells. Depletion of nuclear FOXA2 occurring in islets of type 2 diabetics may thus contribute to reduced islet ACE2 levels. Grant Funding Source : Supported by NIH/NIDDK (DK084466)