Feedback regulation of retinaldehyde reductase DHRS3, a critical determinant of retinoic acid homeostasis.

Retinoic acid is crucial for vertebrate embryogenesis, influencing anterior-posterior patterning and organogenesis through its interaction with nuclear hormone receptors comprising heterodimers of retinoic acid receptors (RARα, β, or γ) and retinoid X receptors (RXRα, β, or γ). Tissue retinoic acid levels are tightly regulated since both its excess and deficiency are deleterious. Dehydrogenase/reductase 3 (DHRS3) plays a critical role in this regulation by converting retinaldehyde to retinol, preventing excessive retinoic acid formation.

Expression and biochemical analyses of proteins involved in the transport of carotenoids and retinoids.

Animals acquire carotenoids from the diet and convert them to retinoids. These lipids must be distributed in the body to support retinoid signaling in peripheral tissues and photoreceptor function in the eyes. However, the hydrophobicity of carotenoids and retinoids limit their diffusion in the aqueous environment of the body.

Carotenoid modifying enzymes in metazoans.

Carotenoids constitute an essential dietary component of animals and other non-carotenogenic species which use these pigments in both their modified and unmodified forms. Animals utilize uncleaved carotenoids to mitigate light damage and oxidative stress and to signal fitness and health. Carotenoids also serve as precursors of apocarotenoids including retinol, and its retinoid metabolites, which carry out essential functions in animals by forming the visual chromophore 11-cis-retinaldehyde.

Regenerating Skeletal Muscle Compensates for the Impaired Macrophage Functions Leading to Normal Muscle Repair in Retinol Saturase Null Mice.

Skeletal muscle repair is initiated by local inflammation and involves the engulfment of dead cells (efferocytosis) by infiltrating macrophages at the injury site. Macrophages orchestrate the whole repair program, and efferocytosis is a key event not only for cell clearance but also for triggering the timed polarization of the inflammatory phenotype of macrophages into the healing one. While pro-inflammatory cytokines produced by the inflammatory macrophages induce satellite cell proliferation and differentiation into myoblasts, healing macrophages initiate the resolution of inflammation, angiogenesis, and extracellular matrix formation and drive myoblast fusion and myotube growth.

Mechanisms of Feedback Regulation of Vitamin A Metabolism.

Vitamin A is an essential nutrient required throughout life. Through its various metabolites, vitamin A sustains fetal development, immunity, vision, and the maintenance, regulation, and repair of adult tissues. Abnormal tissue levels of the vitamin A metabolite, retinoic acid, can result in detrimental effects which can include congenital defects, immune deficiencies, proliferative defects, and toxicity.

Role of cellular retinol-binding protein, type 1 and retinoid homeostasis in the adult mouse heart: A multi-omic approach.

The main active metabolite of Vitamin A, all-trans retinoic acid (RA), is required for proper cellular function and tissue organization. Heart development has a well-defined requirement for RA, but there is limited research on the role of RA in the adult heart. Homeostasis of RA includes regulation of membrane receptors, chaperones, enzymes, and nuclear receptors.

Multi-omic Analysis of Non-human Primate Heart after Partial-body Radiation with Minimal Bone Marrow Sparing.

High-dose radiation exposure results in hematopoietic and gastrointestinal acute radiation syndromes followed by delayed effects of acute radiation exposure, which encompasses multiple organs, including heart, kidney, and lung. Here we sought to further characterize the natural history of radiation-induced heart injury via determination of differential protein and metabolite expression in the heart. We quantitatively profiled the proteome and metabolome of left and right ventricle from non-human primates following 12 Gy partial body irradiation with 2.

Identifying vitamin A signaling by visualizing gene and protein activity, and by quantification of vitamin A metabolites.

Vitamin A (retinol) is an essential nutrient for embryonic development and adult homeostasis. Signaling by vitamin A is carried out by its active metabolite, retinoic acid (RA), following a two-step conversion. RA is a small, lipophilic molecule that can diffuse from its site of synthesis to neighboring RA-responsive cells where it binds retinoic acid receptors within RA response elements of target genes.

A retrospective cohort study evaluating correlates of deep tissue infections among patients enrolled in opioid agonist treatment using administrative data in Ontario, Canada.

Objective: The objective of this study was to evaluate the relationship between individual characteristics and deep tissue infections in patients enrolled in opioid agonist treatment in Ontario, Canada.

Methods: A retrospective cohort study was conducted on patients in opioid agonist treatment between January 1, 2011, and December 31, 2015 in Ontario, Canada. Patients were identified using data from the Ontario Health Insurance Plan Database, and the Ontario Drug Benefit Plan Database.

Role of carotenoids and retinoids during heart development.

The nutritional requirements of the developing embryo are complex. In the case of dietary vitamin A (retinol, retinyl esters and provitamin A carotenoids), maternal derived nutrients serve as precursors to signaling molecules such as retinoic acid, which is required for embryonic patterning and organogenesis. Despite variations in the composition and levels of maternal vitamin A, embryonic tissues need to generate a precise amount of retinoic acid to avoid congenital malformations.

Retinol Saturase Knock-Out Mice are Characterized by Impaired Clearance of Apoptotic Cells and Develop Mild Autoimmunity.

Apoptosis and the proper clearance of apoptotic cells play a central role in maintaining tissue homeostasis. Previous work in our laboratory has shown that when a high number of cells enters apoptosis in a tissue, the macrophages that engulf them produce retinoids to enhance their own phagocytic capacity by upregulating several phagocytic genes. Our data indicated that these retinoids might be dihydroretinoids, which are products of the retinol saturase (RetSat) pathway.

Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair.

The vitamin A metabolite, retinoic acid, is an important signaling molecule during embryonic development serving critical roles in morphogenesis, organ patterning and skeletal and neural development. Retinoic acid is also important in postnatal life in the maintenance of tissue homeostasis, while retinoid-based therapies have long been used in the treatment of a variety of cancers and skin disorders. As the number of people living with chronic disorders continues to increase, there is great interest in extending the use of retinoid therapies in promoting the maintenance and repair of adult tissues.

Recent insights on the role and regulation of retinoic acid signaling during epicardial development.

The vitamin A metabolite, retinoic acid, carries out essential and conserved roles in vertebrate heart development. Retinoic acid signals via retinoic acid receptors (RAR)/retinoid X receptors (RXRs) heterodimers to induce the expression of genes that control cell fate specification, proliferation, and differentiation. Alterations in retinoic acid levels are often associated with congenital heart defects.

Alterations in retinoic acid signaling affect the development of the mouse coronary vasculature.

Background: During the final stages of heart development the myocardium grows and becomes vascularized by means of paracrine factors and cell progenitors derived from the epicardium. There is evidence to suggest that retinoic acid (RA), a metabolite of vitamin A, plays an important role in epicardial-based developmental programming. However, the consequences of altered RA-signaling in coronary development have not been systematically investigated.

Hippo Signaling Plays an Essential Role in Cell State Transitions during Cardiac Fibroblast Development.

During development, progenitors progress through transition states. The cardiac epicardium contains progenitors of essential non-cardiomyocytes. The Hippo pathway, a kinase cascade that inhibits the Yap transcriptional co-factor, controls organ size in developing hearts.

Retinoic acid signaling promotes the cytoskeletal rearrangement of embryonic epicardial cells.

All- trans-retinoic acid (RA), a vitamin A metabolite, is an important signaling molecule required for the proper development of the heart. The epicardium is the main source of RA in the embryonic heart, yet the cardiogenic functions of epicardial-produced RA are not fully understood. Here, we investigated the roles of RA signaling in the embryonic epicardium using in vivo and in vitro models of excess or deficiency of RA.

Retinol saturase modulates lipid metabolism and the production of reactive oxygen species.

Retinol saturase (RetSat) catalyzes the saturation of double bonds of all-trans-retinol leading to the production of dihydroretinoid metabolites. Beside its role in retinoid metabolism, there is evidence that RetSat modulates the cellular response to oxidative stress and plays critical roles in adipogenesis and the accumulation of lipids. Here, we explore the relationship between RetSat, lipid metabolism and oxidative stress using in vitro and in vivo models with altered expression of RetSat.

New insights and changing paradigms in the regulation of vitamin A metabolism in development.

Vitamin A and its active metabolite retinoic acid are essential for embryonic development and adult homeostasis. Surprisingly, excess or deficiency of vitamin A and retinoic acid can cause similar developmental defects. Therefore, strict feedback and other mechanisms exist to regulate the levels of retinoic acid within a narrow physiological range.

Hyperglycemia and redox status regulate RUNX2 DNA-binding and an angiogenic phenotype in endothelial cells.

Angiogenesis is regulated by hyperglycemic conditions, which can induce cellular stress responses, reactive oxygen species (ROS), and anti-oxidant defenses that modulate intracellular signaling to prevent oxidative damage. The RUNX2 DNA-binding transcription factor is activated by a glucose-mediated intracellular pathway, plays an important role in endothelial cell (EC) function and angiogenesis, and is a target of oxidative stress. RUNX2 DNA-binding and EC differentiation in response to glucose were conserved in ECs from different tissues and inhibited by hyperglycemia, which stimulated ROS production through the aldose reductase glucose-utilization pathway.

Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times.

Retinoic acid (RA) is a terpenoid that is synthesized from vitamin A/retinol (ROL) and binds to the nuclear receptors retinoic acid receptor (RAR)/retinoid X receptor (RXR) to control multiple developmental processes in vertebrates. The available clinical and experimental data provide uncontested evidence for the pleiotropic roles of RA signaling in development of multiple embryonic structures and organs such eyes, central nervous system, gonads, lungs and heart. The development of any of these above-mentioned embryonic organ systems can be effectively utilized to showcase the many strategies utilized by RA signaling.

The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development.

Oxidation of retinol via retinaldehyde results in the formation of the essential morphogen all-trans-retinoic acid (ATRA). Previous studies have identified critical roles in the regulation of embryonic ATRA levels for retinol, retinaldehyde, and ATRA-oxidizing enzymes; however, the contribution of retinaldehyde reductases to ATRA metabolism is not completely understood. Herein, we investigate the role of the retinaldehyde reductase Dhrs3 in embryonic retinoid metabolism using a Dhrs3-deficient mouse.

Structure/function relationships of adipose phospholipase A2 containing a cys-his-his catalytic triad.

Adipose phospholipase A(2) (AdPLA or Group XVI PLA(2)) plays an important role in the onset of obesity by suppressing adipose tissue lipolysis. As a consequence, AdPLA-deficient mice are resistant to obesity induced by a high fat diet or leptin deficiency. It has been proposed that AdPLA mediates its antilipolytic effects by catalyzing the release of arachidonic acid.

ISX is a retinoic acid-sensitive gatekeeper that controls intestinal beta,beta-carotene absorption and vitamin A production.

The uptake of dietary lipids from the small intestine is a complex process that depends on the activities of specific membrane receptors with yet unknown regulatory mechanisms. Using both mouse models and human cell lines, we show here that intestinal lipid absorption by the scavenger receptor class B type 1 (SR-BI) is subject to control by retinoid signaling. Retinoic acid via retinoic acid receptors induced expression of the intestinal transcription factor ISX.

Increased adiposity in the retinol saturase-knockout mouse.

The enzyme retinol saturase (RetSat) catalyzes the saturation of all-trans-retinol to produce (R)-all-trans-13,14-dihydroretinol. As a peroxisome proliferator-activated receptor (PPAR) gamma target, RetSat was shown to be required for adipocyte differentiation in the 3T3-L1 cell culture model. To understand the mechanism involved in this putative proadipogenic effect of RetSat, we studied the consequences of ablating RetSat expression on retinoid metabolism and adipose tissue differentiation in RetSat-null mice.