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BBA - Molecular and Cell Biology of Lipids (v.1821, #1)

Reviewer Acknowledgment (pp. iii-iv).

Editorial Board (pp. i).

Retinoid and Lipid Metabolism by Ouliana Ziouzenkova Guest Editor; Earl H. Harrison Guest Editor (pp. 1-2).

Retinoid chemistry: Synthesis and application for metabolic disease by Robert W. Curley Jr. (pp. 3-9).

In this review a discussion of the usual procedures used to synthesize retinoids is followed by an overview of the structure–activity relationships of these molecules. The discussion is then focused on the role and impact of retinoids on metabolic disorders with a particular emphasis on obesity, diabetes, and the metabolic syndrome. In these areas, both natural and synthetic retinoids that are being studied are reviewed and areas where likely future research will occur are suggested. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► General synthetic methods for retinoids. ► Natural and synthetic retinoids in metabolic disease. ► Obesity, diabetes and the metabolic syndrome. ► RXR-specific retinoids and metabolic disease.

Keywords: Abbreviations; ROL; retinol; RAL; retinal; RA; retinoic acid; RXR; retinoid X receptor; HWE; Horner–Wadsworth–Emmons; TTNPB; 4-[(1; E; )-2-(5, 5, 8, 8-tetramethyl-5, 6, 7, 8-tetrahydro-2-naphthalenyl)-1-propen-1-yl]benzoic acid; RAR; retinoic acid receptor; 4-HPR; N; -(4-hydroxyphenyl)retinamide; PPAR; peroxisome proliferator-activated receptor; RALdh1; retinal dehydrogenase-1; LXR; liver X receptor; 3-Cl-AHPC; (; E; )-4-[3-(1-Adamantyl)-4-hydroxyphenyl]-3-chlorocinnamic acid; SRBP; serum retinol bonding protein; ROR; retinoid-related orphan receptorRetinoid; Synthesis; Structure–activity relationship; Metabolic disease; Obesity; Diabetes

Analysis, occurrence, and function of 9-cis-retinoic acid by Maureen A. Kane (pp. 10-20).

Metabolic conversion of vitamin A (retinol) into retinoic acid (RA) controls numerous physiological processes. 9-cis-retinoic acid (9cRA), an active metabolite of vitamin A, is a high affinity ligand for retinoid X receptor (RXR) and also activates retinoic acid receptor (RAR). Despite the identification of candidate enzymes that produce 9cRA and the importance of RXRs as established by knockout experiments, in vivo detection of 9cRA in tissue was elusive until recently when 9cRA was identified as an endogenous pancreas retinoid by validated liquid chromatography–tandem mass spectrometry (LC–MS/MS) methodology. This review will discuss the current status of the analysis, occurrence, and function of 9cRA. Understanding both the nuclear receptor-mediated and non-genomic mechanisms of 9cRA will aid in the elucidation of disease physiology and possibly lead to the development of new retinoid-based therapeutics. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► Review of methodology needed to measure endogenous levels of 9- cis-retinoic acid. ► Description of reports of physiological occurrence of 9-cis-retinoic acid. ► Discussion of both receptor-mediated and non-genomic mechanisms of action of 9-cis-retinoic acid.

Keywords: 9-cis-retinoic acid; Retinoic acid; RXR; Retinoid; Analysis; Mass spectrometry

The retinoid X receptors and their ligands by Marcia I. Dawson; Zebin Xia (pp. 21-56).

This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand-bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945–2010).Display Omitted► Retinoid X receptor (RXR) α, β, and γ structural and molecular biology. ► RXR nuclear and cytoplasmic function and binding partners. ► RXR posttranscriptional processing. ► Impact of ligand on cofactor binding. ► Recently identified RXR ligands.

Keywords: Coactivator; Corepressor; Ligand; Ligand-binding domain; Retinoid X receptor; RXR

Modulation of RXR function through ligand design by Perez Efrén Pérez; William Bourguet; Hinrich Gronemeyer; Angel R. de Lera (pp. 57-69).

As the promiscuous partner of heterodimeric associations, retinoid X receptors (RXRs) play a key role within the Nuclear Receptor (NR) superfamily. Some of the heterodimers (PPAR/RXR, LXR/RXR, FXR/RXR) are “permissive” as they become transcriptionally active in the sole presence of either an RXR-selective ligand (“rexinoid”) or a NR partner ligand. In contrast, “non-permissive” heterodimers (including RAR/RXR, VDR/RXR and TR/RXR) are unresponsive to rexinoids alone but these agonists superactivate transcription by synergizing with partner agonists. Despite their promiscuity in heterodimer formation and activation of multiple pathways, RXR is a target for drug discovery. Indeed, a rexinoid is used in the clinic for the treatment of cutaneous T-cell lymphoma. In addition to cancer RXR modulators hold therapeutical potential for the treatment of metabolic diseases. The modulation potential of the rexinoid (as agonist or antagonist ligand) is dictated by the precise conformation of the ligand–receptor complexes and the nature and extent of their interaction with co-regulators, which determine the specific physiological responses through transcription modulation of cognate gene networks. Notwithstanding the advances in this field, it is not yet possible to predict the correlation between ligand structure and physiological response. We will focus on this review on the modulation of PPARγ/RXR and LXR/RXR heterodimer activities by rexinoids. The genetic and pharmacological data from animal models of insulin resistance, diabetes and obesity demonstrate that RXR agonists and antagonists have promise as anti-obesity agents. However, the treatment with rexinoids raises triglycerides levels, suppresses the thyroid hormone axis, and induces hepatomegaly, which has complicated the development of these compounds as therapeutic agents for the treatment of type 2 diabetes and insulin resistance. The discovery of PPARγ/RXR and LXR/RXR heterodimer-selective rexinoids, which act differently than PPARγ or LXR agonists, might overcome some of these limitations.► RXRs are promiscuous partners in heterodimers with other nuclear receptors. ► Permissive heterodimers are responsive to ligands of each partner. ► Ligand structure is linked to cofactor interactions and physiological function. ► Rexinoids are promising drugs for the treatment of the Metabolic Syndrome. ► RXR/PPARγ and RXR/LXR heterodimer-specific rexinoids have been developed.

Keywords: Rexinoid; RXR modulator; PPAR/RXR heterodimer; LXR/RXR heterodimer

Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids by Earl H. Harrison (pp. 70-77).

Vitamin A is an essential nutrient for humans and is converted to the visual chromophore, 11-cis-retinal, and to the hormone, retinoic acid. Vitamin A in animal-derived foods is found as long chain acyl esters of retinol and these are digested to free fatty acids and retinol before uptake by the intestinal mucosal cell. The retinol is then reesterified to retinyl esters for incorporation into chlylomicrons and absorbed via the lymphatics or effluxed into the portal circulation facilitated by the lipid transporter, ABCA1. Provitamin A carotenoids such as β-carotene are found in plant-derived foods. These and other carotenoids are transported into the mucosal cell by scavenger receptor class B type I (SR-BI). Provitamin A carotenoids are partly converted to retinol by oxygenase and reductase enzymes and the retinol so produced is available for absorption via the two pathways described above. The efficiency of vitamin A and carotenoid intestinal absorption is determined by the regulation of a number of proteins involved in the process. Polymorphisms in genes for these proteins lead to individual variability in the metabolism and transport of vitamin A and carotenoids. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► Molecular mechanisms of dietary retinyl ester digestion are reviewed. ► Mechanisms of intestinal absorption of carotenoids and vitamin A are reviewed. ► A number of proteins regulate intestinal absorption of vitamin A and carotenoids.

Keywords: Abbreviations; ARAT; acyl; CoA; retinol acyltransferase; BCO1; β-carotene 15,15′-oxygenase; BCO2; β-carotene 9′10′-oxygenase 2; β-C; β-carotene; α-C; α-carotene; CEL; carboxyl ester lipase; CEL KO, CEL; knockout mice; CRBP; cellular retinol-binding protein; CM; chylomicrons; DGAT; diacylglycerol acyltransferase; KO; knock out; LRAT; lecithin:retinol acyltransferase; LUT; lutein; LYC; lycopene; OA; oleic acid; PTL; pancreatic triglyceride lipase; PLRP; pancreatic lipase-related protein; RA; retinoic acid; REH; retinyl ester hydrolase; RE; retinyl esters; TG; triglycerides; TC; taurocholate; VLDL; very low density lipoproteins; WT; wild type; ZEA; zeaxanthinRetinoid; Carotenoid; Membrane transport; Lipid; Chylomicron; Metabolism

Mammalian Carotenoid-oxygenases: Key players for carotenoid function and homeostasis by Glenn P. Lobo; Jaume Amengual; Grzegorz Palczewski; Darwin Babino; Johannes von Lintig (pp. 78-87).

Humans depend on a dietary intake of lipids to maintain optimal health. Among various classes of dietary lipids, the physiological importance of carotenoids is still controversially discussed. On one hand, it is well established that carotenoids, such as β,β-carotene, are a major source for vitamin A that plays critical roles for vision and many aspects of cell physiology. On the other hand, large clinical trials have failed to show clear health benefits of carotenoids supplementation and even suggest adverse health effects in individuals at risk of disease. In recent years, key molecular players for carotenoid metabolism have been identified, including an evolutionarily well conserved family of carotenoid-oxygenases. Studies in knockout mouse models for these enzymes revealed that carotenoid metabolism is a highly regulated process and that this regulation already takes place at the level of intestinal absorption. These studies also provided evidence that β,β-carotene conversion can influence retinoid-dependent processes in the mouse embryo and in adult tissues. Moreover, these analyses provide an explanation for adverse health effects of carotenoids by showing that a pathological accumulation of these compounds can induce oxidative stress in mitochondria and cell signaling pathways related to disease. Advancing knowledge about carotenoid metabolism will contribute to a better understanding of the biochemical and physiological roles of these important micronutrients in health and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

Keywords: Abbreviations; C/EBPα; CCAAT/enhancer-binding protein α; BCMO1; β,β-carotene-15,15′-monooxygenase 1; BCDO2; β,β-carotene-9,10-dioxygenase 2; CCE; carotenoid cleaving enzyme; CD36 (SCARB3); Cluster of Differentiation 36; FABP4 (aP2); fatty acid-binding protein 4; FHR; fenretinide; HPLC; high-performance liquid chromatography; iWAT; inguinal white adipose tissue; PPAR; peroxisome proliferator-activated receptor; SR-BI; scavenger receptor class B type I; RAL; all-; trans; -retinal; RA; all-; trans; -retinoic acid; RAR; retinoic acid receptor; RXR; retinoid X receptor; RetSat; retinol saturase; RPE65; retinal pigment epithelium 65; kDa protein; RE; retinyl esters; ROS; reactive oxygen species; TG; triacylglycerol; VAD; vitamin A-deficient diet; VAS; vitamin A-sufficient diet; WT; wild typeCarotenoid; Retinoid; Carotenoid-oxygenase; Metabolism; Oxidative stress

Maternal–fetal transfer and metabolism of vitamin A and its precursor β-carotene in the developing tissues by Elizabeth Spiegler; Youn-Kyung Kim; Lesley Wassef; Varsha Shete; Loredana Quadro (pp. 88-98).

The requirement of the developing mammalian embryo for retinoic acid is well established. Retinoic acid, the active form of vitamin A, can be generated from retinol and retinyl ester obtained from food of animal origin, and from carotenoids, mainly β-carotene, from vegetables and fruits. The mammalian embryo relies on retinol, retinyl ester and β-carotene circulating in the maternal bloodstream for its supply of vitamin A. The maternal–fetal transfer of retinoids and carotenoids, as well as the metabolism of these compounds in the developing tissues are still poorly understood. The existing knowledge in this field has been summarized in this review in reference to our basic understanding of the transport and metabolism of retinoids and carotenoids in adult tissues. The need for future research on the metabolism of these essential lipophilic nutrients during development is highlighted. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.► Maternal serum retinol, retinyl ester and β-carotene supply vitamin A to the embryo. ► Retinoid homeostasis is maintained in the developing tissues. ► Intact β-carotene can be used as a local source of retinoic acid in the developing tissues.

Keywords: Abbreviations; ROH; retinol; RE; retinyl ester; RA; retinoic acid; RAL; retinaldehyde; bC; β-carotene; dpc; days post coitumβ-carotene; Retinoid; β-carotene cleavage enzyme; Developing tissue; Retinol-binding protein (RBP); Maternal–fetal metabolism

Membrane receptors and transporters involved in the function and transport of vitamin A and its derivatives by Hui Sun (pp. 99-112).

The eye is the human organ most sensitive to vitamin A deficiency because of vision's absolute and heavy dependence on vitamin A for light perception. Studies of the molecular basis of vision have provided important insights into the intricate mechanistic details of the function, transport and recycling of vitamin A and its derivatives (retinoid). This review focuses on retinoid-related membrane receptors and transporters. Three kinds of mammalian membrane receptors and transporters are discussed: opsins, best known as vitamin A-based light sensors in vision; ABCA4, an ATP-dependent transporter specializes in the transport of vitamin A derivative; and STRA6, a recently identified membrane receptor that mediates cellular uptake of vitamin A. The evolutionary driving forces for their existence and the wide spectrum of human diseases associated with these proteins are discussed. Lessons learned from the study of the visual system might be useful for understanding retinoid biology and retinoid-related diseases in other organ systems as well. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► Visual cycle provides a wealth of information on retinoid function and transport. ► Despite their ability to diffuse, transporters for vitamin A derivatives do exist. ► Retinoid-related diseases can be heavily influenced by environmental factors. ► Examples of unsolved questions in the field are presented.

Keywords: Vitamin A; Retinoid; STRA6; Retinol binding protein; Opsin; ABCA4

Retinyl ester hydrolases and their roles in vitamin A homeostasis by Renate Schreiber; Ulrike Taschler; Karina Preiss-Landl; Nuttaporn Wongsiriroj; Robert Zimmermann; Achim Lass (pp. 113-123).

In mammals, dietary vitamin A intake is essential for the maintenance of adequate retinoid (vitamin A and metabolites) supply of tissues and organs. Retinoids are taken up from animal or plant sources and subsequently stored in form of hydrophobic, biologically inactive retinyl esters (REs). Accessibility of these REs in the intestine, the circulation, and their mobilization from intracellular lipid droplets depends on the hydrolytic action of RE hydrolases (REHs). In particular, the mobilization of hepatic RE stores requires REHs to maintain steady plasma retinol levels thereby assuring constant vitamin A supply in times of food deprivation or inadequate vitamin A intake. In this review, we focus on the roles of extracellular and intracellular REHs in vitamin A metabolism. Furthermore, we will discuss the tissue-specific function of REHs and highlight major gaps in the understanding of RE catabolism. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► For the maintenance of constant vitamin A supply retinyl ester hydrolases are required. ► This review summarizes the current knowledge on the roles of retinyl ester hydrolyses in vitamin A metabolism. ► In addition, it discusses tissue-specific functions of retinyl ester hydrolases and highlights major gaps in the understanding of retinyl ester catabolism.

Keywords: Abbreviations; 13cIMH; 13-; cis; isomerohydrolase; ARAT; acyl-CoA:retinol acyltransferase; AREH; acid retinyl ester hydrolase; ATGL; adipose triglyceride lipase; BBB; blood-brain-barrier; BPL-B; brush-border phospholipase B; CE; cholesteryl ester; CEL; carboxyl ester lipase; CES; carboxylesterase; CGI-58; comparative gene identification 58; CM; chylomicron; CRBP1; cellular retinol-binding protein 1; DGAT1; acyl-CoA:diacylglycerol acyltransferase 1; ER; endoplasmic reticulum; Es2; esterase 2; Es3; esterase 3; Es4; esterase 4; Es10; esterase 10; Es22; esterase 22; FA; fatty acid; GPIHBP1; glycosylphosphatidylinositol-anchored high-density-lipoprotein binding protein 1; GS2; gene sequence 2; HL; hepatic lipase; HSC; hepatic stellate cell; HSL; hormone-sensitive lipase; HSPG; heparan sulphate proteoglycan; ko; knock-out; LD; lipid droplet; LRAT; lecithin:retinol acyltransferase; LRP-1; low-density lipoprotein-receptor protein 1; LPL; lipoprotein lipase; MG; monoacylglycerol; MGL; monoglyceride lipase; NREH; neutral retinyl ester hydrolase; PL; phospholipid; PLRP2; pancreatic lipase-related protein 2; PNPLA; patatin-like phospholipase domain containing; PTL; pancreatic triglyceride lipase; RA; retinoic acid; RARα/β; retinoic acid receptor; alpha; /; beta; RBP4; retinol-binding protein 4; RPE; retinal pigment epithelium; RXRα/β/γ; retinoid X receptor; alpha; /; beta; /; gamma; RE; retinyl ester; REH; retinyl ester hydrolase; STRA6; stimulated by retinoic acid gene 6; STS; steroid sulfatase; TG; triacylglycerol; TIP47; tail-interacting protein of 47; kDa; VLDL; very low-density lipoprotein; wt; wild-typeVitamin A; Retinyl ester hydrolase; Lipid droplet; Mobilization; Neutral lipid; Store

Hepatic metabolism of retinoids and disease associations by Yohei Shirakami; Seung-Ah Lee; Robin D. Clugston; William S. Blaner (pp. 124-136).

The liver is the most important tissue site in the body for uptake of postprandial retinoid, as well as for retinoid storage. Within the liver, both hepatocytes and hepatic stellate cells (HSCs) are importantly involved in retinoid metabolism. Hepatocytes play an indispensable role in uptake and processing of dietary retinoid into the liver, and in synthesis and secretion of retinol-binding protein (RBP), which is required for mobilizing hepatic retinoid stores. HSCs are the central cellular site for retinoid storage in the healthy animal, accounting for as much as 50–60% of the total retinoid present in the entire body. The liver is also an important target organ for retinoid actions. Retinoic acid is synthesized in the liver and can interact with retinoid receptors which control expression of a large number of genes involved in hepatic processes. Altered retinoid metabolism and the accompanying dysregulation of retinoid signaling in the liver contribute to hepatic disease. This is related to HSCs, which contribute significantly to the development of hepatic disease when they undergo a process of cellular activation. HSC activation results in the loss of HSC retinoid stores and changes in extracellular matrix deposition leading to the onset of liver fibrosis. An association between hepatic disease progression and decreased hepatic retinoid storage has been demonstrated. In this review article, we summarize the essential role of the liver in retinoid metabolism and consider briefly associations between hepatic retinoid metabolism and disease. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► Hepatocytes are responsible for the uptake and processing of postprandial retinoid into the liver. ► Hepatocytes secrete retinol-binding protein (RBP) from the liver and account for most RBP found in the circulation. ► Extrahepatic tissues store retinoid and can recycle this retinoid back to the liver. ► Hepatic stellate cells store more than 50% of all retinoid present in the body. ► Hepatic retinoid stores are lost during the development of hepatic diseases.

Keywords: Retinoic acid; Hepatocyte; Hepatic stellate cell; Retinyl ester; Retinol-binding protein (RBP); Liver disease

Key enzymes of the retinoid (visual) cycle in vertebrate retina by Philip D. Kiser; Marcin Golczak; Akiko Maeda; Krzysztof Palczewski (pp. 137-151).

A major goal in vision research over the past few decades has been to understand the molecular details of retinoid processing within the retinoid (visual) cycle. This includes the consequences of side reactions that result from delayed all- trans-retinal clearance and condensation with phospholipids that characterize a variety of serious retinal diseases. Knowledge of the basic retinoid biochemistry involved in these diseases is essential for development of effective therapeutics. Photoisomerization of the 11- cis-retinal chromophore of rhodopsin triggers a complex set of metabolic transformations collectively termed phototransduction that ultimately lead to light perception. Continuity of vision depends on continuous conversion of all- trans-retinal back to the 11- cis-retinal isomer. This process takes place in a series of reactions known as the retinoid cycle, which occur in photoreceptor and RPE cells. All- trans-retinal, the initial substrate of this cycle, is a chemically reactive aldehyde that can form toxic conjugates with proteins and lipids. Therefore, much experimental effort has been devoted to elucidate molecular mechanisms of the retinoid cycle and all- trans-retinal-mediated retinal degeneration, resulting in delineation of many key steps involved in regenerating 11- cis-retinal. Three particularly important reactions are catalyzed by enzymes broadly classified as acyltransferases, short-chain dehydrogenases/reductases and carotenoid/retinoid isomerases/oxygenases. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.► Great progress has been made in understanding enzymes of the retinoid cycle. ► Animal models are invaluable in elucidating functions of these enzymes. ► Genetic lesions have linked retinoid cycle enzymes with human retinal diseases. ► Structural data has provided mechanistic insights into retinoid cycle enzymology.

Keywords: RPE65; Retinol dehydrogenase; Visual cycle; Retinoid cycle; Retinal degeneration; Lecithin:retinol acyltransferase

Physiological insights into all- trans-retinoic acid biosynthesis by Joseph L. Napoli (pp. 152-167).

All- trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer, and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy balance and obesity has increased considerably, especially concerning postnatal function. atRA action depends on atRA biosynthesis: defects in retinoid-dependent processes increasingly relate to defects in atRA biogenesis. Considerable evidence indicates that physiological atRA biosynthesis occurs via a regulated process, consisting of a complex interaction of retinoid binding-proteins and retinoid recognizing enzymes. An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. Each of these enzymes associates with explicit biological processes mediated by atRA. Redundancy occurs, but seems limited. Cumulative data support a model of interactions among these enzymes with retinoid binding-proteins, with feedback regulation and/or control by atRA via modulating gene expression of multiple participants. The ratio apo-CRBP1/holo-CRBP1 participates by influencing retinol flux into and out of storage as retinyl esters, thereby modulating substrate to support atRA biosynthesis. atRA biosynthesis requires the presence of both an RDH and an RALDH: conversely, absence of one isozyme of either step does not indicate lack of atRA biosynthesis at the site. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.► Retinoid binding-proteins chaperone atRA biogenesis and function. ► Retinol dehydrogenases (short-chain dehydrogenase gene family) catalyze atRA biogenesis. ► Multiple Rdh and Radlh (Aldh gene family) catalyze contribute to atRA biosynthesis. ► atRA regulates its biosynthesis via redirecting retinol into retinyl esters.

Keywords: Abbreviations; ADH; medium-chain alcohol dehydrogenase(s); ALDH; aldehyde dehydrogenase(s); ARAT; acyl-CoA:retinol acyltransferase; atRA; all-; trans; -retinoic acid; CRABP; cellular retinoic acid binding-protein(s); CRBP; cellular retinol binding-protein(s); FABP; fatty acid binding protein; LRAT; lecithin:retinol acyltransferase; RAR; retinoic acid receptor(s); RBP; serum retinol binding-protein; RDH; retinol dehydrogenase; RE; retinyl ester(s); REH; retinyl ester hydrolase; RRD; retinal reductase; SDR; short-chain dehydrogenase/reductase; STRA; (gene) stimulated by RA; WT; wild-typeRetinol; Retinoic acid; Cellular retinol binding-protein; Lecithin:retinol acyltransferase; Retinol dehydrogenase; Short-chain dehydrogenase/reductase

Signaling by vitamin A and retinol-binding protein in regulation of insulin responses and lipid homeostasis by Daniel C. Berry; Noa Noy (pp. 168-176).

Vitamin A, retinol, circulates in blood bound to serum retinol binding protein (RBP) and is transported into cells by a membrane protein termed stimulated by retinoic acid 6 (STRA6). It was reported that serum levels of RBP are elevated in obese rodents and humans, and that increased level of RBP in blood causes insulin resistance. A molecular mechanism by which RBP can exert such an effect is suggested by the recent discovery that STRA6 is not only a vitamin A transporter but also functions as a surface signaling receptor. Binding of RBP–ROH to STRA6 induces the phosphorylation of a tyrosine residue in the receptor C-terminus, thereby activating a JAK/STAT signaling cascade. Consequently, in STRA6-expressing cells such as adipocytes, RBP–ROH induces the expression of STAT target genes, including SOCS3, which suppresses insulin signaling, and PPARγ, which enhances lipid accumulation. RBP–retinol thus joins the myriad of cytokines, growth factors and hormones which regulate gene transcription by activating cell surface receptors that signal through activation of Janus kinases and their associated transcription factors STATs. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► Holo-RBP, which transports vitamin A in blood, is a signaling molecule. ► STRA6 functions both as a vitamin A transporter and as a surface signaling receptor activated by holo-RBP. ► Activation of STRA6 by RBP–ROH triggers a JAK/STAT cascade, thereby inducing gene trascription. ► Some genes induced by RBP–ROH/STRA6/JAK/STAT signaling are involved in regulating insulin responses and lipid metabolism.

Keywords: Retinol binding protein; JAK/STAT; STRA6; Obesity; Insulin resistance

Lipid metabolism in mammalian tissues and its control by retinoic acid by M. Luisa Bonet; Joan Ribot; Andreu Palou (pp. 177-189).

Evidence has accumulated that specific retinoids impact on developmental and biochemical processes influencing mammalian adiposity including adipogenesis, lipogenesis, adaptive thermogenesis, lipolysis and fatty acid oxidation in tissues. Treatment with retinoic acid, in particular, has been shown to reduce body fat and improve insulin sensitivity in lean and obese rodents by enhancing fat mobilization and energy utilization systemically, in tissues including brown and white adipose tissues, skeletal muscle and the liver. Nevertheless, controversial data have been reported, particularly regarding retinoids' effects on hepatic lipid and lipoprotein metabolism and blood lipid profile. Moreover, the molecular mechanisms underlying retinoid effects on lipid metabolism are complex and remain incompletely understood. Here, we present a brief overview of mammalian lipid metabolism and its control, introduce mechanisms through which retinoids can impact on lipid metabolism, and review reported activities of retinoids on different aspects of lipid metabolism in key tissues, focusing on retinoic acid. Possible implications of this knowledge in the context of the management of obesity and the metabolic syndrome are also addressed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► Treatment with all-trans retinoic acid reduces body fat and improves insulin sensitivity in mice by promoting fat mobilisation and catabolism. ► Retinoid-induced hypertriglyceridemia is, however, frequently encountered in humans and animal models. ► There is an intimate cross-talk between retinoid and lipid metabolism. ► Molecular mechanisms of retinoid effects on lipid metabolism are complex and not fully understood.

Keywords: Abbreviations; ACC; acetyl-coA carboxylase; ACOX; acyl-CoA oxidase; AMPK; AMP-activated protein kinase; atRA; all-trans retinoic acid; BAT; brown adipose tissue; BCMO1; β,β-carotene monooxygenase 1; C/EBP; CCAAT-enhancer binding protein; CAC; carnitine/acylcarnitine carrier; ChREBP; carbohydrate response element binding protein; CPT1; carnitine palmitoyltransferase 1; CRABP-II; cellular retinoic acid-binding protein II; DNL; de novo lipogenesis; FABP5; fatty acid-binding protein 5; FAS; fatty acid synthase; HSL; hormone sensitive lipase; LPL; lipoprotein lipase; LXR; liver X receptor; MCAD; medium-chain acyl-CoA dehydrogenase; p38 MAPK; p38 mitogen-activated protein kinase; PPAR; peroxisome proliferator-activated receptor; PGC-1; PPAR gamma coactivator 1; PPRE; PPAR response element; pRb; retinoblastoma protein; RA; retinoic acid; Rald; retinaldehyde; Raldh; retinaldehyde dehydrogenase; RAR; retinoic acid receptor; RARE; retinoic acid response element; RXR; retinoid X receptor; SREBP-1; sterol regulatory element binding protein-1; TTNPB; 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl]benzoic acid; UCP; uncoupling protein; VLDL; very low density lipoprotein; WAT; white adipose tissueRetinoic acid; Adipogenesis; Lipogenesis; Lipolysis; Thermogenesis; Obesity

The contribution of vitamin A to autocrine regulation of fat depots by Rumana Yasmeen; Shanmugam M. Jeyakumar; Barbara Reichert; Fangping Yang; Ouliana Ziouzenkova (pp. 190-197).

Morbidity and mortality associated with increased white fat accumulation in visceral fat depots have focused attention on the pathways regulating the development of this tissue during embryogenesis, in adulthood, and while under the influence of obesogenic diets. Adipocytes undergo clonal expansion, differentiation (adipogenesis) and maturation through a complex network of transcriptional factors, most of which are expressed at similar levels in visceral and subcutaneous fat. Rigorous research attempts to unfold the pathways regulating expression and activity of adipogenic transcription factors that act in a fat-depot-specific manner. Peroxisome proliferator-activated receptor-γ (PPARγ) is the master regulator of adipogenesis, and is expressed at higher levels in subcutaneous than in visceral depots. PPARγ expression in adipogenesis is mediated by CCAAT/enhancer binding proteins (C/EBPs) and several transcription factors acting in conjunction with C/EBPs, although alternative pathways through zinc-finger protein-423 (ZFP423) transcription factor are sufficient to induce PPARγ expression and adipogenesis. Vitamin A and its metabolites, retinaldehyde and retinoic acid, are transcriptionally-active molecules. Retinoic acid is generated from retinaldehyde in adipose tissue by the aldehyde dehydrogenase-1 family of enzymes (Aldh1). In this review, we discuss the role of Aldh1 enzymes in the generation of retinoic acid during adipogenesis, in the regulation of the transcriptional network of PPARγ in a fat-depot-specific manner, and the important contribution of this autocrine pathway in the development of visceral obesity. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► Fat accumulation in visceral fat depots increases risks for morbidity and mortality. ► The autocrine role of aldehyde dehydrogenase-1 family of enzymes in the regulation of the transcriptional network in a fat-depot-specific manner and in the development of visceral obesity is discussed.

Keywords: Abdominal obesity; Raldh1; Aldh1a2; Aldh1a3; Omental; ZFP423

Alcohol and aldehyde dehydrogenases: Retinoid metabolic effects in mouse knockout models by Sandeep Kumar; Lisa L. Sandell; Paul A. Trainor; Frank Koentgen; Gregg Duester (pp. 198-205).

Retinoic acid (RA) is the active metabolite of vitamin A (retinol) that controls growth and development. The first step of RA synthesis is controlled by enzymes of the alcohol dehydrogenase (ADH) and retinol dehydrogenase (RDH) families that catalyze oxidation of retinol to retinaldehyde. The second step of RA synthesis is controlled by members of the aldehyde dehydrogenase (ALDH) family also known as retinaldehyde dehydrogenase (RALDH) that further oxidize retinaldehyde to produce RA. RA functions as a ligand for DNA-binding RA receptors that directly regulate transcription of specific target genes. Elucidation of the vitamin A metabolic pathway and investigation of the endogenous function of vitamin A metabolites has been greatly improved by development of mouse ADH, RDH, and RALDH loss-of-function models. ADH knockouts have demonstrated a postnatal role for this enzyme family in clearance of excess retinol to prevent vitamin A toxicity and in generation of RA for postnatal survival during vitamin A deficiency. A point mutation in Rdh10 generated by ethylnitrosourea has demonstrated that RDH10 generates much of the retinaldehyde needed for RA synthesis during embryonic development. Raldh1, Raldh2, and Raldh3 knockouts have demonstrated that RALDH1, RALDH2, and RALDH3 generate most of the RA needed during embryogenesis. These mouse models serve as instrumental tools for providing new insight into retinoid function. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.► This review focuses on the enzymes that convert vitamin A (retinol) to retinoic acid. ► Alcohol dehydrogenases and retinol dehydrogenases convert retinol to retinaldehyde. ► Retinaldehyde dehydrogenases metabolize retinaldehyde to retinoic acid. ► We discuss mouse models carrying loss-of-function mutations for these enzymes. ► These mouse models have been instrumental for understanding vitamin A function.

Keywords: Retinol; Retinaldehyde; Retinoic acid; Alcohol dehydrogenase; Retinol dehydrogenase; Retinaldehyde dehydrogenase

Chromatin remodeling and epigenetic regulation of the CrabpI gene in adipocyte differentiation by Li-Na Wei (pp. 206-212).

Retinoic acid (RA) acts by binding to nuclear RA receptors (RARs) to regulate a broad spectrum of downstream target genes in most cell types examined. In cytoplasm, RA binds specifically to cellular retinoic acid binding proteins I (CRABPI), and II. Although the function of CRABPI in animals remains the subject of debate, it is believed that CRABPI binding facilitates RA metabolism, thereby modulating the concentration of RA and the type of RA metabolites in cells. The basal promoter of the CrabpI gene is a housekeeping promoter that can be regulated by thyroid hormones (T3), DNA methylation, sphinganine, and ethanol acting on its upstream regulatory region. T3 regulation of CrabpI is mediated by the binding of thyroid hormone receptor (TR) to a TR response element (TRE) approximately 1 kb upstream of the basal promoter. Specifically, in the adipocyte differentiation process, T3 regulation is bimodal and closely associated with the cellular differentiation status: T3 activates CrabpI in predifferentiated cells (e.g., mesenchymal precursors or fibroblasts), but suppresses this gene once cells are committed to adipocyte differentiation. These disparate effects are functions of T3-triggered differential recruitment of coregulatory complexes in conjunction with chromatin looping/folding that alters the configuration of this genomic locus along adipocyte differentiation. Subsequent sliding, disassembly and reassembly of nucleosomes occur, resulting in specific changes in the conformation of the basal promoter chromatin at different stages of differentiation. This chapter summarizes studies illustrating the epigenetic regulation of CrabpI expression during adipocyte differentiation. Understanding the pathways regulating CrabpI in this specific context might help to illuminate the physiological role of CRABPI in vivo. This article is part of a special issue entitled: Retinoid and Lipid Metabolism.► T3 regulates CrabpI gene in a bimodal fashion during adipocyte differentiation. ► TRAP220 is responsible for T3 activation of CrabpI gene in preadipocyte. ► RIP140 is responsible for T3 repression of CrabpI gene in differentiating adipocyte. ► Epigenetic regulation of CrabpI gene involves chromatin folding and nucleosome rearrangement on its regulatory region. ► Chromatin remodeling underlies epigenetic regulation of CrabpI gene during adipocyte differentiation.

Keywords: Abbreviations; 3C; Chromosome conformation capture; ChIP; chromatin immunoprecipitation; CRABP; cellular retinoic acid binding protein; EC; embryonal carcinoma; LM-PCR; ligation mediated polymerase chain reaction; MNase; micrococcal nuclease; RA; retinoic acid; RAR; retinoic acid receptor; RIP140; receptor interacting protein 140; TIS; transcription initiation site; TR; thyroid hormone receptor; TRAP220; thyroid hormone receptor activating protein 220; TRE; thyroid hormone response elementCRABPI; Retinoic acid; Thyroid hormone; RIP140. TRAP220; Chromatin remodeling

Emerging roles for retinoids in regeneration and differentiation in normal and disease states by Lorraine J. Gudas (pp. 213-221).

The vitamin A (retinol) metabolite, all-trans retinoic acid (RA), is a signaling molecule that plays key roles in the development of the body plan and induces the differentiation of many types of cells. In this review the physiological and pathophysiological roles of retinoids (retinol and related metabolites) in mature animals are discussed. Both in the developing embryo and in the adult, RA signaling via combinatorial Hox gene expression is important for cell positional memory. The genes that require RA for the maturation/differentiation of T cells are only beginning to be cataloged, but it is clear that retinoids play a major role in expression of key genes in the immune system. An exciting, recent publication in regeneration research shows that ALDH1a2 (RALDH2), which is the rate-limiting enzyme in the production of RA from retinaldehyde, is highly induced shortly after amputation in the regenerating heart, adult fin, and larval fin in zebrafish. Thus, local generation of RA presumably plays a key role in fin formation during both embryogenesis and in fin regeneration. HIV transgenic mice and human patients with HIV-associated kidney disease exhibit a profound reduction in the level of RARβ protein in the glomeruli, and HIV transgenic mice show reduced retinol dehydrogenase levels, concomitant with a greater than 3-fold reduction in endogenous RA levels in the glomeruli. Levels of endogenous retinoids (those synthesized from retinol within cells) are altered in many different diseases in the lung, kidney, and central nervous system, contributing to pathophysiology. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► RA signaling via Hox expression is important for cell positional memory. ► ALDH1a2 (RALDH2) is induced after amputation in the regenerating heart and fin in zebrafish. ► Endogenous retinoids are altered in many different diseases in adult animals.

Keywords: Dendritic cell; Emphysema; Epigenetics; Intestine; Regeneration; Stem cell

Endogenous retinoids in the hair follicle and sebaceous gland by Helen B. Everts (pp. 222-229).

Vitamin A and its derivatives (retinoids) are critically important in the development and maintenance of multiple epithelial tissues, including skin, hair, and sebaceous glands, as shown by the detrimental effects of either vitamin A deficiency or toxicity. Thus, precise levels of retinoic acid (RA, active metabolite) are needed. These precise levels of RA are achieved by regulating several steps in the conversion of dietary vitamin A (retinol) to RA and RA catabolism. This review discusses the localization of RA synthesis to specific sites within the hair follicle and sebaceous gland, including their stem cells, during both homeostasis and disease states. It also discusses what is known about the specific roles of RA within the hair follicle and sebaceous gland. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.► The pilosebaceous unit consists of a hair follicle and sebaceous gland. ► The pilosebaceous unit requires precise levels of retinoic acid. ► Retinoic acid synthesis localized to the pilosebaceous unit, including stem cells. ► Mechanisms of action of retinoic acid within the pilosebaceous unit are emerging. ► But much more information has yet to be discovered.

Keywords: Abbreviations; RA; retinoic acid; atRA; all-trans retinoic acid; 9cRA; 9-cis retinoic acid; 13cRA; 13-cis retinoic acid; PSU; pilosebaceous unit; IFE; interfollicular epidermisRetinoic acid; Synthesis; Retinoid; Hair follicle; Stem cells; Sebaceous gland

Retinoid metabolism and its effects on the vasculature by Eun-Jung Rhee; Shriram Nallamshetty; Jorge Plutzky (pp. 230-240).

Retinoids, the metabolically-active structural derivatives of vitamin A, are critical signaling molecules in many fundamental biological processes including cell survival, proliferation and differentiation. Emerging evidence, both clinical and molecular, implicates retinoids in atherosclerosis and other vasculoproliferative disorders such as restenosis. Although the data from clinical trials examining effect of vitamin A and vitamin precursors on cardiac events have been contradictory, this data does suggest that retinoids do influence fundamental processes relevant to atherosclerosis. Preclinical animal model and cellular studies support these concepts. Retinoids exhibit complex effects on proliferation, growth, differentiation and migration of vascular smooth muscle cells (VSMC), including responses to injury and atherosclerosis. Retinoids also appear to exert important inhibitory effects on thrombosis and inflammatory responses relevant to atherogenesis. Recent studies suggest retinoids may also be involved in vascular calcification and endothelial function, for example, by modulating nitric oxide pathways. In addition, established retinoid effects on lipid metabolism and adipogenesis may indirectly influence inflammation and atherosclerosis. Collectively, these observations underscore the scope and complexity of retinoid effects relevant to vascular disease. Additional studies are needed to elucidate how context and metabolite-specific retinoid effects affect atherosclerosis. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.► Retinoids, derivatives of vitamin A, control fundamental cellular processes. ► In this review, we examine the complex effects of retinoids on the vasculature. ► Retinoids modulate vascular injury, inflammation, and thrombosis in atherogenesis. Further work is needed to define the scope of retinoid effects on vascular disease.

Keywords: Abbreviations; ADH; alcohol dehydrogenase; ADMA; asymmetric dimethylarginine; AP-1; activated protein-1; apo14; β-apo-14′-carotenal; ARVM; adult rat ventricular myocytes; ATBC; Alpha-tocopherol Beta-carotene Cancer Prevention Study; atRA; all-trans retinoic acid; BCO-I; β,β-carotene-15,15′-monooxygenase; BCO-II; β,β-carotene-9′,10′-dioxygenase; bFGF; basic fibroblast growth factor; CARET; Beta-Carotene and Retinol Efficacy Trial; CAD; coronary artery disease; CMEC; cultured microvascular endothelial cells; CRABP; cellular retinoic acid binding protein; CRBP; cellular retinol binding protein; CRP; C-reactive protein; CYP26; cytochrome P450 family 26; DBD; DNA binding domain; DC; dendritic cell; eNOS; endothelial nitric oxide synthase; ESC; embryonic stem cells; FXR; farnesoid X receptor; GM-CSF; granulocyte-macrophage colony-stimulating factor; HAT; histone acetyltransferase; HDAC; histone deacetylase; HUVEC; human umbilical vein endothelial cell; IL; interleukin; iNOS; inducible nitric oxide synthase; KLF; Krüppel-like zinc-finger transcription factor 5; LBD; ligand binding domain; LPS; lipopolysaccharide; LXR; liver X receptor; mfn-2; mitofusin 2; MGP; matrix Gla protein; MHC; major histocompatibility complex; miR; microRNA; NOS; nitric oxide synthase; OPG; osteoprotegerin; PAI-1; plasminogen activator inhibitor-1; PDGF; platelet-derived growth factor; PKC; protein kinase C; PMA; phorbol-12-myristate-13-acetate; PPAR; peroxisome proliferator-activated receptor; PRIME; Prospective Epidemiological Study of Myocardial Infarction; RA; retinoic acid; RALD; retinaldehyde; RALDH; retinaldehyde dehydrogenase; RANKL; receptor-activator of NF-κB; RAR; retinoic acid receptor; RARE; retinoic acid response element; RARRES1; retinoic acid receptor responder-1; RBP; retinol-binding protein; RXR; retinoid X receptor; SDR; short-chain dehydrogenases/reductases; T2D; type 2 diabetes mellitus; T; _H; -cell; helper T cell; TNF; tumor necrosis factor; tPA; tissue plasminogen activator; tTG; tissue transglutaminase; TTR; transthyretin; VCAM; vascular cell adhesion molecule; VDRE; vitamin D response element; VSMC; vascular smooth muscle cellRetinoid; Vascular smooth muscle cell; RXR; RAR; Inflammation; Atherosclerosis

Hiding in plain sight: Uncovering a new function of vitamin A in redox signaling by Beatrice Hoyos; Rebeca Acin-Perez; Donald A. Fischman; Giovanni Manfredi; Ulrich Hammerling (pp. 241-247).

The protein kinase Cδ signalosome modulates the generation of acetyl-Coenzyme A from glycolytic sources. This module is composed of four interlinked components: PKCδ, the signal adapter p66Shc, cytochrome c, and vitamin A. It resides in the intermembrane space of mitochondria, and is at the center of a feedback loop that senses upstream the redox balance between oxidized and reduced cytochrome c as a measure of the workload of the respiratory chain, and transmits a forward signal to the pyruvate dehydrogenase complex to adjust the flux of fuel entering the tricarboxylic acid cycle. The novel role of vitamin A as co-activator and potential electron carrier, required for redox activation of PKCδ, is discussed. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.► PKCδ, p66Shc, cytochrome C and vitamin A form a mitochondrial signal module. ► The PKCδ signalosome senses and adjusts the workload of the respiratory chain. ► The PKCδ signalosome signals the pyruvate dehydrogenase complex to adjust fuel flux. ► Vitamin A serves as co-factor and electron carrier for redox activation of PKCδ.

Keywords: Vitamin A; Mitochondrion; Protein kinase Cδ; Energy homeostasis

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