Hnf1α is required for proper gut epithelial endocrine cell specification and controls the mTOR signalling pathway in mice

Abstract

Although roles for Hnf1α are well characterized in the pancreas and liver, its precise function within the maintenance of intestinal homeostasis remains mostly unknown. We aimed to determine the role for this transcriptional regulator in this context. Loss of Hnf1α in mice results in a disturbance of intestinal epithelial cell lineages functions, increased crypt proliferation and intestinalomegaly during adult life. We show that Hnf1α is an important regulator of the mucosal barrier function and lumen‐to‐blood glucose delivery. The intestine of Hnf1α null mice display impaired endocrine cell differentiation with a decrease in gastric inhibitory polypeptide and an increase in ghrelin expression, both gut specific hormones directly involved in glucose and energy homeostasis. A similar impact is observed on proper Paneth cell differentiation with abnormalities in the granule exocytosis pathway. Finally, we identify the Ddit4l/REDD2 inhibitor of the mammalian target of rapamycin (mTOR) to be down modulated in the small intestine of adult Hnf1α mutant mice. This observation correlates with the abnormal sustained activation of the mTOR signalling pathway at the reach of adulthood. Together, these results unravel a novel role for Hnf1α in sustaining the maturation of secretory cell lineages and in regulating intestinal growth through the mTOR signalling pathway. This work was supported by the CIHR