Blocking hepatocyte retinoic acid signaling increases hepatic retinol-RBP4 secretion and disrupts vitamin A homeostasis in mice.

Vitamin A is an essential micronutrient with broad physiological roles. The liver is of central importance in whole-body vitamin A homeostasis, with hepatocytes distributing retinol to the rest of the body by secreting it in complex with Retinol-binding protein 4 (RBP4). The goal of this study was to elucidate homeostatic mechanisms regulating hepatic vitamin A metabolism by specifically blocking retinoic acid (RA) signaling in hepatocytes. Herein, we used Albumin-Cre (AlbCre) mice to conditionally express a dominant negative retinoic acid receptor (Rardn) in hepatocytes, generating AlbCre:Rardn mice. These mice experience a functional block in hepatocyte RA signaling, as evidenced by the suppression of Cyp26a1, a gene that is highly responsive to RA and is exclusively expressed in hepatocytes within the liver. Unexpectedly, we observed increased circulating levels of retinol and RBP4 in AlbCre:Rardn mice, accompanied by increased hepatic expression of RBP4 at the gene and protein level. We then compared the effect of blocking RA signaling in AlbCre:Rardn mice with a more physiological depletion of hepatic retinoid content, using a mouse model of diet-induced vitamin A deficiency. Similar to AlbCre:Rardn mice, hepatic RBP4 protein expression was higher in vitamin A deficient mice. However, this was instead accompanied by no transcriptional change in hepatic Rbp4 and reduced retinol-RBP4 in the plasma, indicating an overall reduction in hepatic retinol-RBP4 secretion. Together, these data provide new insight into factors that modulate circulating retinol-RBP4 levels, and how the liver supplies the rest of the body with vitamin A.