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 RBP4 (Retinol-binding protein 4). 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 ( Alb Cre ) mice to conditionally express a dominant negative retinoic acid receptor ( Rar dn ) in hepatocytes, generating Alb Cre :Rar dn mice. These mice experience a functional block in hepatocyte RA signalling, 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 Alb Cre :Rar dn mice, accompanied by increased hepatic expression of RBP4 at the gene and protein level. We then compared the effect of blocking RA signaling in Alb Cre :Rar dn mice with a more physiological depletion of hepatic retinoid content, using a mouse model of diet-induced vitamin A deficiency. Similar to Alb Cre :Rar dn 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.