Retinoic Acid and Its Nuclear Receptors in Health and Disease

We are interested in understanding linkages between vitamin A metabolism and actions and chronic disease development, specifically metabolic disease and acute lung disease. Our research has used knockout and transgenic mouse models to study vitamin A actions in facilitating and regulating insulin secretion. Early studies explored the role of all-trans-retinoic acid [ATRA] in glucose stimulated insulin secretion, using a transgenic mouse that expressed specifically in pancreatic β-cells a dominant-negative retinoic acid receptor-α [RARdn] transgene that ablated most retinoic acid receptor [RAR] and ATRA signaling in these cells. These studies established that ATRA-RAR signaling is required for maintaining normal glucose-stimulated insulin secretion and for maintaining β-cell mass within the endocrine pancreas. Recently, our focus has shifted to ATRA-RAR actions in enteroendocrine cells [EECs] present within the small intestine. We have focused specifically on the incretin-secreting K- and L-cells, which respectively secrete glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide-1 [GLP-1]. GIP and GLP-1 are hormones secreted in response to nutrient arrival in the gut and they signal β-cells to secrete insulin. We studied mice that lack retinol-binding protein 2 [RBP2], which show elevated GIP secretion in response to an oral fat challenge. RBP2 plays a role in channeling substrate retinol towards ATRA formation. These investigations identified a role for ATRA-RAR in facilitating GIP release from K-cells. Our findings establish further that ATRA-RAR signaling is needed to assure normal differentiation of K-cells within intestinal crypts and along the crypt-villus axis. We are presently continuing our investigations of retinoid actions in EEC biology aiming to identify the processes through which ATRA-RAR signaling affects GIP release into blood in response to nutrient signals. Recently, we initiated investigations in mice into the importance of ATRA-RAR signaling in the response of the lung to experimentally-induced acute respiratory distress [ARD]. We have focused on identifying ATRA-RAR actions in cells residing in the alveolar niche; lung lipofibroblasts [LFs], in alveolar epithelial type 2 cells [AEC2s] and in vascular endothelial cells [ECs] The current understanding of vitamin A biology in these cells is that hepatic vitamin A stores are mobilized as retinol bound to retinol-binding protein 4 (RBP4) and delivered through the circul