William S. Blaner

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 natural and synthetic analogs) are required by most tissues for maintaining the normal health of the tissue. This is certainly true for the pancreas. The recent literature is convincing that retinoids are needed by the adult to assure normal pancreatic endocrine functions, especially those of the alpha- and beta-cells. It is also well established that retinoids are required to insure normal pancreas development in utero, including the development of the endocrine pancreas. The actions of retinoids for maintaining normal pancreatic islet functions has drawn considerable research interest from investigators interested in understanding and treating metabolic disease. Pancreatic retinoids are also of interest to investigators studying the origins of pancreatic disease, including the development of pancreatic fibrosis and its sequelae. This research interest is focused on pancreatic stellate cells (PSCs) which store retinoids and possess the metabolic machinery needed to metabolize retinoids. The literature on pancreatic disease and retinoids suggests that there is an association between impairments in pancreatic retinoid storage and metabolism and the development of pancreatic disease. These topics will be considered in this review.

DGAT1-deficiency affects the cellular distribution of hepatic retinoid and attenuates the progression of CCl4-induced liver fibrosis

Dietary carotenoids like β-carotene are converted within the body either to retinoid, via β-carotene-15,15′-dioxygenase (BCO1), or to β-apo-carotenoids, via β-carotene-9′,10′-oxygenase 2. Some β-apo-carotenoids are potent antagonists of retinoic acid receptor (RAR)-mediated transcriptional regulation, which is required to ensure normal heart development and functions. We established liquid chromatography tandem mass spectrometery methods for measuring concentrations of 10 β-apo-carotenoids in mouse plasma, liver, and heart and assessed how these are influenced by Bco1 deficiency and β-carotene intake. Surprisingly, Bco1^−/−mice had an increase in heart levels of retinol, nonesterified fatty acids, and ceramides and a decrease in heart triglycerides. These lipid changes were accompanied by elevations in levels of genes important to retinoid metabolism, specifically retinol dehydrogenase 10 and retinol-binding protein 4, as well as genes involved in lipid metabolism, including peroxisome proliferator-activated receptor-γ, lipoprotein lipase, Cd36, stearoyl-CoA desaturase 1, and fatty acid synthase. We also obtained evidence of compromised heart function, as assessed by two-dimensional echocardiography, in Bco1^−/−mice. However, the total absence of Bco1 did not substantially affect β-apo-carotenoid concentrations in the heart. β-Carotene administration to matched Bco1^−/−and wild-type mice elevated total β-apo-carotenal levels in the heart, liver, and plasma and total β-apo-carotenoic acid levels in the liver. Thus, BCO1 modulates heart metabolism and function, possibly by altering levels of cofactors required for the actions of nuclear hormone receptors.

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 β‐cells of adult mice. atRA signaling was ablated in β‐cells by overexpressing a dominant‐negative retinoic acid receptor (RAR)‐α 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 β‐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 β‐cell mass and insulin per β‐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 β‐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 β‐cell mass. FASEB J . 29, 671‐683 (2015). www.fasebj.org

Vitamin A status is an important consideration in the health of both wild and captive amphibians. Data concerning whole body vitamin A homeostasis in amphibians are scarce, although these animals have been used as experimental models to study the actions of vitamin A in vision, limb regeneration and embryogenesis. The available data suggest that many aspects of vitamin A biology in amphibians are similar to the canonical characteristics of vitamin A metabolism and actions established in mammals. This is consistent with the evolutionary conservation of these important biological processes. Amphibians must obtain vitamin A in their diet, with captive animals being prone to vitamin A deficiency. There is still much to be learned about vitamin A biology in amphibians that can only be achieved through rigorous scientific research. Improved understanding of amphibian vitamin A biology will aid the conservation of endangered amphibians in the wild, as well as the successful maintenance of ex situ populations. Zoo Biol. 33:527–535, 2014. © 2014 Wiley Periodicals Inc.