Retinol and retinyl esters: biochemistry and physiology
2013; Elsevier BV; Volume: 54; Issue: 7 Linguagem: Inglês
10.1194/jlr.r037648
ISSN1539-7262
AutoresSheila M. O’Byrne, William S. Blaner,
Tópico(s)melanin and skin pigmentation
ResumoBy definition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insufficient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include efficient mechanisms to acquire vitamin A from the diet, efficient and overlapping mechanisms for the transport of vitamin A in the circulation, a specific mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review. By definition, a vitamin is a substance that must be obtained regularly from the diet. Vitamin A must be acquired from the diet, but unlike most vitamins, it can also be stored within the body in relatively high levels. For humans living in developed nations or animals living in present-day vivariums, stored vitamin A concentrations can become relatively high, reaching levels that can protect against the adverse effects of insufficient vitamin A dietary intake for six months, or even much longer. The ability to accumulate vitamin A stores lessens the need for routinely consuming vitamin A in the diet, and this provides a selective advantage to the organism. The molecular processes that underlie this selective advantage include efficient mechanisms to acquire vitamin A from the diet, efficient and overlapping mechanisms for the transport of vitamin A in the circulation, a specific mechanism allowing for vitamin A storage, and a mechanism for mobilizing vitamin A from these stores in response to tissue needs. These processes are considered in this review. Since the identification of fat-soluble A a century ago (1McCollum E.V. Davis M. The necessity of certain lipins in the diet during growth.J. Biol. Chem. 1913; 15: 167-175Abstract Full Text PDF Google Scholar), retinoids (vitamin A and its natural and synthetic analogs) have been the most extensively studied of the fat-soluble vitamins. This research has identified essential roles for retinoids in many different aspects of mammalian physiology, including embryonic development, adult growth and development, maintenance of immunity, maintenance of epithelial barriers, and vision (1McCollum E.V. Davis M. The necessity of certain lipins in the diet during growth.J. Biol. Chem. 1913; 15: 167-175Abstract Full Text PDF Google Scholar, 2Gudas L. Sporn M.B. Roberts A.B. Cellular biology and biochemistry of the retinoids.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 443-520Google Scholar, 3Wald G. Molecular basis of visual excitation.Science. 1968; 162: 230-239Crossref PubMed Google Scholar, 4Saari J.C. Retinoids in mammalian vision.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 563-588Crossref Google Scholar, 5Ross A.C. Hammerling U. Retinoids and the immune system.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 521-544Google Scholar). This review focuses on retinoid biochemistry in mammals, primarily on retinol and retinyl ester metabolism. However, we also consider other retinol metabolites, including retro- and anhydro-retinoids and retinoid-β-glucuronides. The different retinoid forms present within the body (see Fig. 1) are generated by and large through modifications to the terminal polar end group of the molecule. Retinol and retinyl esters are the most abundant retinoid forms present in the body. All-trans-retinol is by definition vitamin A. When a fatty acyl group is esterified to the hydroxyl terminus of retinol, a storage form of retinol, the retinyl ester, is formed. The most abundant retinyl esters present in the body are those of palmitic acid, oleic acid, stearic acid, and linoleic acid (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar). Although retinyl acetate can be found in supplements to foods and vitamin formulations, only long-chain acyl groups are esterified to retinol by animals. Retinyl esters have no known biological activity aside from retinol storage and for serving as the substrate for the formation of the visual chromophore 11-cis-retinal, which must be formed from all-trans-retinyl ester through linked hydrolysis and isomerization reactions catalyzed by the enzyme RPE65 (3Wald G. Molecular basis of visual excitation.Science. 1968; 162: 230-239Crossref PubMed Google Scholar, 4Saari J.C. Retinoids in mammalian vision.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 563-588Crossref Google Scholar, 8Travis G.H. Golczak M. Moise A.R. Palczewski K. Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents.Annu. Rev. Pharmacol. Toxicol. 2007; 47: 469-512Crossref PubMed Scopus (293) Google Scholar, 9Palczewski K. Chemistry and biology of vision.J. Biol. Chem. 2012; 287: 1612-1619Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar). Retinol is a transport form and a precursor form, which is enzymatically activated to retinoic acid via a two-step oxidation process. The primary role of retinal is in the eye where 11-cis-retinal is needed for visual pigment formation. In tissues, retinal serves as an intermediate in the synthesis of retinoic acid from retinol (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar). The literature also suggests a direct role for retinal in adipose tissue, where it was shown to inhibit adipogenesis and suppress peroxisome proliferator-activated receptor-γ (PPARγ) and retinoid X receptor (RXR) responses in cell culture models and in mouse models fed high-fat diets (10Ziouzenkova O. Orasanu G. Sharlach M. Akiyama T.E. Berger J.P. Viereck J. Hamilton J.A. Tang G. Dolnikowski G.G. Vogel S. et al.Retinaldehyde represses adipogenesis and diet-induced obesity.Nat. Med. 2007; 13: 695-702Crossref PubMed Scopus (273) Google Scholar). The all-trans- (tretinoin, Retin-A) and 9-cis- (alitretinoin) isomers of retinoic acid are transcriptionally active retinoids and are thought to account for the gene regulatory properties of retinoids within cells and tissues (11Chambon P. The retinoid signaling pathway: molecular and genetic analyses.Semin. Cell Biol. 1994; 5: 115-125Crossref PubMed Google Scholar, 12Mangelsdorf D.J. UK Evans R.M. The retinoid receptors.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 319-350Google Scholar). The concentration of retinoic acid within tissues is generally very low and usually 100 to 1,000 times less than that of retinol (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar). All-trans-retinoic acid can be isomerized through a nonenzymatic process to form the 9-cis- or 13-cis-retinoic acid (isotretinoin, Accutane) isomers (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar). Although 13-cis-retinoic acid is a naturally occurring retinoid, it is less transcriptionally active than either the all-trans- or 9-cis-isomer (11Chambon P. The retinoid signaling pathway: molecular and genetic analyses.Semin. Cell Biol. 1994; 5: 115-125Crossref PubMed Google Scholar, 12Mangelsdorf D.J. UK Evans R.M. The retinoid receptors.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 319-350Google Scholar). The actions of retinoic acid in regulating transcription are considered in detail in this thematic series by Rochette-Egly and colleagues (13Al Tanoury Z. Piskunov A. Rochette-Egly C. Vitamin A and retinoid signaling: genomic and non-genomic effects.J. Lipid Res. 2013; 54: 1761-1775Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Various oxo- and hydroxy- forms of retinol and retinoic acid as well as glucuronides of both retinol and retinoic acid are present in the body, albeit at very low concentrations relative to retinol and retinyl esters (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar). Although some of these oxidized and conjugated retinoid forms may have biologic/transcriptional activity, it appears likely that most of these forms are catabolic in nature and destined for elimination from the body. Since there are no known enzymes that can reduce retinoic acid to retinal, excessive or unneeded retinoic acid is not recycled back to retinol/retinyl ester and must be catabolized and eliminated from the body. This catabolism is catalyzed by one of several cytochrome P450 (CYP) enzymes (14White J.A. Beckett-Jones B. Guo Y.D. Dilworth F.J. Bonasoro J. Jones G. Petkovich M. cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450.J. Biol. Chem. 1997; 272: 18538-18541Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar, 15White J.A. Guo Y.D. Baetz K. Beckett-Jones B. Bonasoro J. Hsu K.E. Dilworth F.J. Jones G. Petkovich M. Identification of the retinoic acid-inducible all-trans-retinoic acid 4-hydroxylase.J. Biol. Chem. 1996; 271: 29922-29927Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar, 16Fujii H. Sato T. Kaneko S. Gotoh O. Fujii-Kuriyama Y. Osawa K. Kato S. Hamada H. Metabolic inactivation of retinoic acid by a novel P450 differentially expressed in developing mouse embryos.EMBO J. 1997; 16: 4163-4173Crossref PubMed Scopus (290) Google Scholar, 17Ray W.J. Bain G. Yao M. Gottlieb D.I. CYP26, a novel mammalian cytochrome P450, is induced by retinoic acid and defines a new family.J. Biol. Chem. 1997; 272: 18702-18708Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar, 18Ross A.C. Retinoid production and catabolism: role of diet in regulating retinol esterification and retinoic acid oxidation.J. Nutr. 2003; 133: 291S-296SCrossref PubMed Google Scholar), giving rise to more water-soluble oxidized and conjugated retinoid forms that can be more easily excreted. These CYPs are discussed in depth by Kedishvili in a review in this thematic review series (19Kedishvili N.Y. Enzymology of retinoic acid biosynthesis and degradation.J. Lipid Res. 2013; 54: 1744-1760Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). The metabolism of retinoids described above and the enzymes responsible for catalyzing this metabolism are summarized in Fig. 2. Retro- and anhydro-retinoids are also naturally occurring retinoid forms that can be synthesized by cells and tissues that are present within the body (20Vakiani E. Buck J. Retro-retinoids: metabolism and action.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 97-115Crossref Google Scholar, 21Moise A.R. Kuksa V. Imanishi Y. Palczewski K. Identification of all-trans-retinol:all-trans-13,14-dihydroretinol saturase.J. Biol. Chem. 2004; 279: 50230-50242Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Enzymes able to catalyze the formation of retro- and anhydro-retinoids have been identified (20Vakiani E. Buck J. Retro-retinoids: metabolism and action.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 97-115Crossref Google Scholar, 21Moise A.R. Kuksa V. Imanishi Y. Palczewski K. Identification of all-trans-retinol:all-trans-13,14-dihydroretinol saturase.J. Biol. Chem. 2004; 279: 50230-50242Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). It has been proposed that the retro- and anhydro-retinoids may have actions in regulating immune function, but the biochemical mechanisms responsible for these actions have not been elucidated (5Ross A.C. Hammerling U. Retinoids and the immune system.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 521-544Google Scholar, 20Vakiani E. Buck J. Retro-retinoids: metabolism and action.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 97-115Crossref Google Scholar, 21Moise A.R. Kuksa V. Imanishi Y. Palczewski K. Identification of all-trans-retinol:all-trans-13,14-dihydroretinol saturase.J. Biol. Chem. 2004; 279: 50230-50242Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). The enzyme responsible for the saturation of the 13-14 double bond of all-trans-retinol to produce all-trans-13,14-dihydroretinol, termed retinoid saturase (RetSat), was described and cloned several years ago (21Moise A.R. Kuksa V. Imanishi Y. Palczewski K. Identification of all-trans-retinol:all-trans-13,14-dihydroretinol saturase.J. Biol. Chem. 2004; 279: 50230-50242Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 22Moise A.R. Kuksa V. Blaner W.S. Baehr W. Palczewski K. Metabolism and transactivation activity of 13,14-dihydroretinoic acid.J. Biol. Chem. 2005; 280: 27815-27825Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 23Moise A.R. Isken A. Dominguez M. de Lera A.R. von Lintig J. Palczewski K. Specificity of zebrafish retinol saturase: formation of all-trans-13,14-dihydroretinol and all-trans-7,8-dihydroretinol.Biochemistry. 2007; 46: 1811-1820Crossref PubMed Scopus (29) Google Scholar). Expression of RetSat is regulated by PPARγ, a key transcriptional regulator of adipogenesis. RetSat activity has been implicated in the regulation of adipocyte development and differentiation. Ablation of RetSat expression in a cell culture model of adipocyte differentiation inhibited adipogenesis, whereas ectopic expression of RetSat enhanced differentiation (24Schupp M. Lefterova M.I. Janke J. Leitner K. Cristancho A.G. Mullican S.E. Qatanani M. Szwergold N. Steger D.J. Curtin J.C. et al.Retinol saturase promotes adipogenesis and is downregulated in obesity.Proc. Natl. Acad. Sci. USA. 2009; 106: 1105-1110Crossref PubMed Scopus (59) Google Scholar). This block in adipocyte differentiation could not be rescued by addition of 13,14-dihydroretinol to the cells, implying that this enzyme may have other, unknown substrates (24Schupp M. Lefterova M.I. Janke J. Leitner K. Cristancho A.G. Mullican S.E. Qatanani M. Szwergold N. Steger D.J. Curtin J.C. et al.Retinol saturase promotes adipogenesis and is downregulated in obesity.Proc. Natl. Acad. Sci. USA. 2009; 106: 1105-1110Crossref PubMed Scopus (59) Google Scholar). Mice totally lacking RetSat exhibit increased adiposity, which is associated with an upregulation of PPARγ (25Moise A.R. Lobo G.P. Erokwu B. Wilson D.L. Peck D. Alvarez S. Dominguez M. Alvarez R. Flask C.A. de Lera A.R. et al.Increased adiposity in the retinol saturase-knockout mouse.FASEB J. 2010; 24: 1261-1270Crossref PubMed Scopus (32) Google Scholar). Future studies may identify other novel metabolites of retinol, possibly generated by RetSat, which may explain these phenotypes. Over the last four decades, many retinoid metabolites have been identified (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar, 20Vakiani E. Buck J. Retro-retinoids: metabolism and action.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 97-115Crossref Google Scholar, 21Moise A.R. Kuksa V. Imanishi Y. Palczewski K. Identification of all-trans-retinol:all-trans-13,14-dihydroretinol saturase.J. Biol. Chem. 2004; 279: 50230-50242Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Some of these are proposed but not proved to have important physiological roles, whereas others are simply catabolic products destined for elimination from the body. It is possible that some of these metabolites may yet prove to be very important physiologically, but we have chosen to consider in our review only those associated with a relatively substantial literature. The reader should turn to earlier review Refs. 6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar, and 20Vakiani E. Buck J. Retro-retinoids: metabolism and action.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 97-115Crossref Google Scholar for more details regarding these other retinoid metabolites. Although the liver and intestine are the major tissue sites of retinol esterification in the body, many tissues are able to esterify retinol and accumulate some retinyl ester stores, including the eye, lung, adipose tissue, testes, skin, and spleen (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. Retinoid uptake, metabolism and transport.The Handbook of Experimental Pharmacology: Retinoids. vol. 139. Springer Verlag, Berlin1999: 31-95Google Scholar). It is now understood that the enzyme responsible for the preponderance of retinyl ester formation in the body is lecithin:retinol acyltransferase (LRAT). This understanding was obtained from study of mutant mice in which the gene encoding LRAT had been totally ablated (26Batten M.L. Imanishi Y. Maeda T. Tu D.C. Moise A.R. Bronson D. Possin D. Van Gelder R.N. Baehr W. Palczewski K. Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver.J. Biol. Chem. 2004; 279: 10422-10432Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 27Liu L. Gudas L.J. Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency.J. Biol. Chem. 2005; 280: 40226-40234Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 28O'Byrne S.M. Wongsiriroj N. Libien J. Vogel S. Goldberg I.J. Baehr W. Palczewski K. Blaner W.S. Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT).J. Biol. Chem. 2005; 280: 35647-35657Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar). Lrat-deficient mice possess significant retinyl ester stores in adipose tissue but not in liver, eyes, lungs, testes, skin, or spleen (26Batten M.L. Imanishi Y. Maeda T. Tu D.C. Moise A.R. Bronson D. Possin D. Van Gelder R.N. Baehr W. Palczewski K. Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver.J. Biol. Chem. 2004; 279: 10422-10432Abstract Full Text Full Text PDF PubMed Scopus (262) Google Scholar, 27Liu L. Gudas L.J. Disruption of the lecithin:retinol acyltransferase gene makes mice more susceptible to vitamin A deficiency.J. Biol. Chem. 2005; 280: 40226-40234Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 28O'Byrne S.M. Wongsiriroj N. Libien J. Vogel S. Goldberg I.J. Baehr W. Palczewski K. Blaner W.S. Retinoid absorption and storage is impaired in mice lacking lecithin:retinol acyltransferase (LRAT).J. Biol. Chem. 2005; 280: 35647-35657Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 29Liu L. Tang X.H. Gudas L.J. Homeostasis of retinol in lecithin:retinol acyltransferase gene knockout mice fed a high retinol diet.Biochem. Pharmacol. 2008; 75: 2316-2324Crossref PubMed Scopus (31) Google Scholar). LRAT catalyzes a transesterification, transferring long-chain fatty acyl moieties (primarily palmitic, stearic, oleic, and linoleic acids) present at the sn-1 position of membrane bilayer phosphatidylcholine to retinol, forming retinyl esters (6Blaner W.S. Olson J.A. Retinol and retinoic acid metabolism.in: Sporn M.B. Roberts A.B. Goodman D.S. The Retinoids: Biology, Chemistry and Medicine. Raven Press Ltd., New York1994: 229-256Google Scholar, 7Vogel S. Gamble M. Blaner W.S. 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The other vertebrate member of this family that is relatively well studied is adipose-specific phospholipase A2 (AdPLA) (36Duncan R.E. Sarkadi-Nagy E. Jaworski K. Ahmadian M. Sul H.S. Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA).J. Biol. Chem. 2008; 283: 25428-25436Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 37Jaworski K. Ahmadian M. Duncan R.E. Sarkadi-Nagy E. Varady K.A. Hellerstein M.K. Lee H.Y. Samuel V.T. Shulman G.I. Kim K.H. et al.AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency.Nat. Med. 2009; 15: 159-168Crossref PubMed Scopus (176) Google Scholar). AdPLA was described by Sul and colleagues as a phospholipase associated with the development of obesity induced by high-fat feeding (37Jaworski K. Ahmadian M. Duncan R.E. Sarkadi-Nagy E. Varady K.A. Hellerstein M.K. Lee H.Y. Samuel V.T. Shulman G.I. Kim K.H. et al.AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency.Nat. Med. 2009; 15: 159-168Crossref PubMed Scopus (176) Google Scholar). The other vertebrate members of this protein family are less well studied and are reported to possess either phospholipase and/or phosphatidylcholine-dependent acyltransferase activities (38Uyama T. Jin X.H. Tsuboi K. Tonai T. Ueda N. Characterization of the human tumor suppressors TIG3 and HRASLS2 as phospholipid-metabolizing enzymes.Biochim. Biophys. Acta. 2009; 1791: 1114-1124Crossref PubMed Scopus (52) Google Scholar, 39Jin X.H. Okamoto Y. Morishita J. Tsuboi K. Tonai T. Ueda N. Discovery and characterization of a Ca2+-independent phosphatidylethanolamine N-acyltransferase generating the anandamide precursor and its congeners.J. Biol. Chem. 2007; 282: 3614-3623Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, 40Uyama T. Morishita J. Jin X.H. Okamoto Y. Tsuboi K. Ueda N. 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Structural basis for the acyltransferase activity of lecithin:retinol acyltransferase-like proteins.J. Biol. Chem. 2012; 287: 23790-23807Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). It should be noted that LRAT is completely distinct from and shares no relationship with lecithin:cholesterol acyltransferase (LCAT). The older literature suggests that another enzymatic activity, acyl-CoA:retinol acyltransferase (ARAT), may be physiologically important for catalyzing retinyl ester formation. ARAT is proposed to esterify retinol using fatty acyl groups present in the acyl-CoA pool (33Ross A.C. Retinol esterification by rat liver microsomes. Evidence for a fatty acyl coenzyme A:retinol acyltransferase.J. Biol. Chem. 1982; 257: 2453-2459Abstract Full Text PDF PubMed Google Scholar). ARAT also is reported to differ from LRAT with regard to its ability to acquire retinol within the cell. 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