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      Retinyl ester hydrolases and their roles in vitamin A homeostasis

      , , , , , *

      Biochimica et Biophysica Acta

      Elsevier Pub. Co

      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-type, Vitamin A, Retinyl ester hydrolase, Lipid droplet, Mobilization, Neutral lipid, Store

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          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.

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          Most cited references 202

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          Liver fibrosis.

          Liver fibrosis is the excessive accumulation of extracellular matrix proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver fibrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. Our knowledge of the cellular and molecular mechanisms of liver fibrosis has greatly advanced. Activated hepatic stellate cells, portal fibroblasts, and myofibroblasts of bone marrow origin have been identified as major collagen-producing cells in the injured liver. These cells are activated by fibrogenic cytokines such as TGF-beta1, angiotensin II, and leptin. Reversibility of advanced liver fibrosis in patients has been recently documented, which has stimulated researchers to develop antifibrotic drugs. Emerging antifibrotic therapies are aimed at inhibiting the accumulation of fibrogenic cells and/or preventing the deposition of extracellular matrix proteins. Although many therapeutic interventions are effective in experimental models of liver fibrosis, their efficacy and safety in humans is unknown. This review summarizes recent progress in the study of the pathogenesis and diagnosis of liver fibrosis and discusses current antifibrotic strategies.
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            Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.

            The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.
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              Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes.

              In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4(-/-) mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.

                Author and article information

                Biochim Biophys Acta
                Biochim. Biophys. Acta
                Biochimica et Biophysica Acta
                Elsevier Pub. Co
                January 2012
                January 2012
                : 1821
                : 1
                : 113-123
                Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31A, 8010 Graz, Austria
                Author notes
                [* ]Corresponding author. Tel.: + 43 316 380 1926; fax: + 43 316 380 9016. achim.lass@
                © 2012 Elsevier B.V.

                This document may be redistributed and reused, subject to certain conditions.



                hspg, heparan sulphate proteoglycan, es22, esterase 22, es10, esterase 10, fa, fatty acid, wt, wild-type, dgat1, acyl-coa:diacylglycerol acyltransferase 1, hsl, hormone-sensitive lipase, er, endoplasmic reticulum, rpe, retinal pigment epithelium, ko, knock-out, pnpla, patatin-like phospholipase domain containing, es2, esterase 2, mgl, monoglyceride lipase, gpihbp1, glycosylphosphatidylinositol-anchored high-density-lipoprotein binding protein 1, crbp1, cellular retinol-binding protein 1, cgi-58, comparative gene identification 58, tip47, tail-interacting protein of 47 kda, areh, acid retinyl ester hydrolase, rarα/β, retinoic acid receptor alpha/beta, lrp-1, low-density lipoprotein-receptor protein 1, mobilization, lpl, lipoprotein lipase, vitamin a, ces, carboxylesterase, store, hl, hepatic lipase, cm, chylomicron, lipid droplet, vldl, very low-density lipoprotein, re, retinyl ester, pl, phospholipid, es4, esterase 4, stra6, stimulated by retinoic acid gene 6, cel, carboxyl ester lipase, ce, cholesteryl ester, mg, monoacylglycerol, nreh, neutral retinyl ester hydrolase, reh, retinyl ester hydrolase, bbb, blood-brain-barrier, ptl, pancreatic triglyceride lipase, hsc, hepatic stellate cell, gs2, gene sequence 2, plrp2, pancreatic lipase-related protein 2, arat, acyl-coa:retinol acyltransferase, sts, steroid sulfatase, lrat, lecithin:retinol acyltransferase, neutral lipid, 13cimh, 13-cis isomerohydrolase, tg, triacylglycerol, atgl, adipose triglyceride lipase, rbp4, retinol-binding protein 4, ra, retinoic acid, bpl-b, brush-border phospholipase b, retinyl ester hydrolase, ld, lipid droplet, rxrα/β/γ, retinoid x receptor alpha/beta/gamma, es3, esterase 3


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