It is well established that chylomicron remnant (dietary) vitamin A is taken up from the circulation by hepatocytes, but more than 80 % of the vitamin A in the liver is stored in hepatic stellate cells (HSC). It presently is not known how vitamin A is transferred from hepatocytes to HSCs for storage. Since retinol-binding protein 4 (RBP4), a protein that is required for mobilizing stored vitamin A, is synthesized solely by hepatocytes and not HSCs, it similarly is not known how vitamin A is transferred from HSCs to hepatocytes. Although it has long been thought that RBP4 is absolutely essential for delivering vitamin A to tissues, recent research has proven that this notion is incorrect since total RBP4-deficiency is not lethal. In addition to RBP4, vitamin A is also found in the circulation bound to lipoproteins and as retinoic acid bound to albumin. It is not known how these different circulating pools of vitamin A contribute to the vitamin A needs of different tissues. In our view, better insight into these three issues is required to better understand vitamin A absorption, storage and mobilization. Here, we provide an up to date synthesis of current knowledge regarding the intestinal uptake of dietary vitamin A, the storage of vitamin A within the liver, and the mobilization of hepatic vitamin A stores, and summarize areas where our understanding of these processes is incomplete.

Retinoids (vitamin A and its analogs) are highly potent regulators of cell differentiation, cell proliferation, and apoptosis. Because of these activities, retinoids have been most extensively studied in the contexts of embryonic development and of proliferative diseases, especially cancer and skin disease. Recently, there has been considerable new research interest focused on gaining understanding of the roles that retinoids and/or retinoid-related proteins may have in the development of metabolic diseases, primarily obesity, diabetes, and dyslipidemia. This review will summarize recent advances that have been made in these areas, focusing on the role of retinoids in modulating adipogenesis, the roles of retinoids and retinoid-related proteins as signaling molecules linking obesity with the development of type II diabetes, the roles of retinoids in pancreatic β-cell biology/insulin secretion, and the actions of retinoids in hepatic steatosis.

Retinoic acid signaling is required for maintaining a range of cellular processes, including cell differentiation, proliferation, and apoptosis. We investigated the actions of all-trans-retinoic acid (atRA) signaling in pancreatic b-cells of adult mice. atRA signaling was ablated in b-cells by overexpressing a dominant-negative retinoic acid receptor (RAR)-a mutant (RARdn) using an inducible Cre-Lox system under the control of the pancreas duodenal homeobox gene promoter. Our studies establish that hypomorphism for RAR in b-cells leads to an age-dependent decrease in plasma insulin in the fed state and in response to a glucose challenge. Glucose-stimulated insulin secretion was also impaired in islets isolated from mice expressing RARdn. Among genes that are atRA responsive, Glut2 and Gck mRNA levels were decreased in isolated islets from RARdn-expressing mice. Histologic analyses of RARdn-expressing pancreata revealed a decrease in b-cell mass and insulin per b-cell 1 mo after induction of the RARdn. Our results indicate that atRA signaling mediated by RARs is required in the adult pancreas for maintaining both b-cell function and mass, and provide insights into molecular mechanisms underlying these actions.-Brun, P.-J., Grijalva, A., Rausch, R., Watson, E., Yuen, J. J., Das, B. C., Shudo, K., Kagechika, H., Leibel, R. L., Blaner, W. S. Retinoic acid receptor signaling is required to maintain glucose-stimulated insulin secretion and b-cell mass. FASEB J. 29, 671-683 (2015). www.fasebj.orgHUMANS AND OTHER VERTEBRATES must acquire retinoids (vitamin A and its metabolites) from the diet in order to maintain normal health (1). Retinoids regulate many cellular processes including cellular proliferation, differentiation, and apoptosis, and hence, they have roles in many essential physiologic processes including the maintenance of immunity, reproduction, and embryonic development (2, 3). These essential actions are thought to be mediated primarily by the all-trans-retinoic acid (atRA) and 9-cis-retinoic acid (9cRA), which regulate transcription by serving as ligands for nuclear hormone receptors (4, 5). atRA serves as the natural ligand for the 3 retinoic acid receptors (RARs; a, b, and g); whereas 9cRA is proposed to be a natural ligand for the 3 retinoid X receptors (RXRs; a, b, and g) (6). Over 500 genes are reported to be responsive to either atRA or 9cRA (7).An extensive literature supports a role for retinoids in the maintenance of pancreatic endocrine functions (8-18). Pancreatic islets express genes encoding retinoland retinoic acid-binding proteins, as well as RARs and RXRs (14,19,20). Isolated pancreatic islets from rats fed a vitamin A-deficient diet display a markedly diminished capacity to secrete insulin in response to a glucose challenge (10). This phenotype was reversed by administering either retinyl ester or atRA to the rats prior to islet isolation. Two recent reports have identified a function for 9cRA and RXR signaling in the regulation of insulin secretion. Using an inducible dominant-ne...

Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. Rbp2-deficient (Rbp2−/−) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young Rbp2−/− mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, Rbp2−/− mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance.

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