Hepatocyte nuclear factors 1α and 1β (HNF1α and HNF1β) are powerful inducers of the enzymatic activity of angiotensin‐converting enzyme 2 (ACE2) in insulin‐secreting cells

Abstract

Maturity onset diabetes of the young (MODY) types 3 and 5 are caused by deficiency of hepatocyte nuclear factor 1α (HNF1α) and hepatocyte nuclear factor 1β (HNF1β) which bind to similar DNA motifs. Our laboratory has previously shown that: 1) pancreatic angiotensin‐converting enzyme 2 (ACE2) is reduced in diabetes, 2) pancreatic ACE2 gene therapy improves glucose control in diabetic mice, and 3) HNF1β induces expression of ACE2 mRNA in insulinoma cells. However, discordance between ACE2 expression at the mRNA and enzyme activity level is often reported. Furthermore, HNF1α is more prevalent and thought to be more important than HNF1β in differentiated beta cells. Hypothesis: Both HNF1α and HNF1β lead to increased ACE2 mRNA expression as well as elevated ACE2 enzymatic activity in insulin‐secreting cells. Transfection of rat 832/13 insulinoma cells with expression plasmids for HNF1α and HNF1β led to marked (25‐ and 95‐fold, respectively, p < 0.001) induction of ACE2 mRNA and a strong increase (12‐ and 41‐fold, p < 0.001) in ACE2 enzymatic activity. Furthermore, HNF1α and HNF1β induced expression from both of the two known ACE2 promoter regions in mouse βTC‐3 insulinoma cells. The data demonstrate a link between HNF1α/HNF1β, ACE2 activity, and glucose homeostasis. These observations could lead to new therapeutic strategies for the treatment of MODY and type 2 diabetes. Support: NIH/NIDDK (DK084466).