Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice

Abstract

The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very long-chain fatty acids (ELOVLs) in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2−/− mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) in both liver and serum, showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24-carbon precursors for DHA and DPAn-6 formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol-regulatory element binding protein 1c (SREBP-1c), as well as its downstream target genes. Surprisingly, the Elovl2−/− mice were resistant to hepatic steatosis and diet-induced weight gain, implying that hepatic DHA synthesis via ELOVL2, in addition to controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP-1c-independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA. The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very long-chain fatty acids (ELOVLs) in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2−/− mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) in both liver and serum, showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24-carbon precursors for DHA and DPAn-6 formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol-regulatory element binding protein 1c (SREBP-1c), as well as its downstream target genes. Surprisingly, the Elovl2−/− mice were resistant to hepatic steatosis and diet-induced weight gain, implying that hepatic DHA synthesis via ELOVL2, in addition to controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP-1c-independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA. As a source of energy and as structural components of membranes, omega-3 (n-3) and omega-6 (n-6) PUFAs have been shown to have significant roles in many biological functions, including immunity, growth, and metabolism in mammals. Dietary PUFAs, and especially DHA, have been shown to influence hepatic liver metabolism and prevent the development of liver steatosis (1Jump D.B. Clarke S.D. Regulation of gene expression by dietary fat.Annu. Rev. Nutr. 1999; 19: 63-90Crossref PubMed Scopus (546) Google Scholar, 2Sekiya M. Yahagi N. Matsuzaka T. Najima Y. Nakakuki M. Nagai R. Ishibashi S. Osuga J. Yamada N. Shimano H. Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression.Hepatology. 2003; 38: 1529-1539Crossref PubMed Scopus (336) Google Scholar, 3González-Périz A. Horrillo R. Ferré N. Gronert K. Dong B. Morán-Salvador E. Titos E. Martínez-Clemente M. López-Parra M. Arroyo V. et al.Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins.FASEB J. 2009; 23: 1946-1957Crossref PubMed Scopus (470) Google Scholar, 4Oosterveer M.H. van Dijk T.H. Tietge U.J. Boer T. Havinga R. Stellaard F. Groen A.K. Kuipers F. Reijngoud D.J. High fat feeding induces hepatic fatty acid elongation in mice.PLoS ONE. 2009; 4: e6066Crossref PubMed Scopus (117) Google Scholar). Nevertheless, the role of endogenously synthesized PUFAs compared with PUFAs taken up from the diet is relatively unknown. In mammals, the synthesis of very long-chain PUFAs requires a dietary supply of the essential precursors of the omega-6 and omega-3 series, linoleic acid, C18:2n-6, and α-linolenic acid, C18:3n-3, respectively (5Burr G.O. Burr M.M. Nutrition classics from The Journal of Biological Chemistry 82:345–67, 1929. A new deficiency disease produced by the rigid exclusion of fat from the diet.Nutr. Rev. 1973; 31: 248-249PubMed Google Scholar). The biosynthesis of PUFAs of the n-6 and n-3 series occurs via sequential desaturation and elongation steps by the Δ5- and Δ6-fatty acid desaturases (FADSs) 1 and 2, and the fatty acid elongation of very long-chain fatty acids (ELOVLs) 5, 2, and 4 (6Guillou H. Zadravec D. Martin P.G. Jacobsson A. The key roles of elongases and desaturases in mammalian fatty acid metabolism: insights from transgenic mice.Prog. Lipid Res. 2010; 49: 186-199Crossref PubMed Scopus (571) Google Scholar). However, the biosynthesis of the omega-6 PUFA C22:5n-6, docosapentaenoic acid (DPA) n-6, and the omega-3 PUFA C22:6n-3, DHA, requires 24-carbon intermediates, which are subsequently desaturated prior to chain shortening through partial β-oxidation, ultimately yielding DPA and DHA (7Sprecher H. Metabolism of highly unsaturated n-3 and n-6 fatty acids.Biochim. Biophys. Acta. 2000; 1486: 219-231Crossref PubMed Scopus (654) Google Scholar, 8Voss A. Reinhart M. Sankarappa S. Sprecher H. The metabolism of 7,10,13,16,19-docosapentaenoic acid to 4,7,10,13,16,19-docosahexaenoic acid in rat liver is independent of a 4-desaturase.J. Biol. Chem. 1991; 266: 19995-20000Abstract Full Text PDF PubMed Google Scholar). ELOVL5 has been proposed to be involved in the elongation of 18- and 20-carbon PUFA substrates, while data indicate that ELOVL2 and ELOVL4 elongate C20–C24 and C26–C34 PUFAs, respectively (9Leonard A.E. Bobik E.G. Dorado J. Kroeger P.E. Chuang L.T. Thurmond J.M. Parker-Barnes J.M. Das T. Huang Y.S. Mukerji P. Cloning of a human cDNA encoding a novel enzyme involved in the elongation of long-chain polyunsaturated fatty acids.Biochem. J. 2000; 350: 765-770Crossref PubMed Scopus (0) Google Scholar, 10Moon Y.A. Shah N.A. Mohapatra S. Warrington J.A. Horton J.D. Identification of a mammalian long chain fatty acyl elongase regulated by sterol regulatory element-binding proteins.J. Biol. Chem. 2001; 276: 45358-45366Abstract Full Text Full Text PDF PubMed Scopus (275) Google Scholar, 11Wang Y. Torres-Gonzalez M. Tripathy S. Botolin D. Christian B. Jump D.B. Elevated hepatic fatty acid elongase-5 activity affects multiple pathways controlling hepatic lipid and carbohydrate composition.J. Lipid Res. 2008; 49: 1538-1552Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 12Gregory M.K. Cleland L.G. James M.J. Molecular basis for differential elongation of omega-3 docosapentaenoic acid by the rat Elovl5 and Elovl2.J. Lipid Res . 2013; 54: 2851-2857Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). While ELOVL5, FADS1, and FADS2 are expressed to a certain extent in all tissues tested, the level of ELOVL2 is significant in liver, testis, uterus, placenta, mammary gland, retina, and certain areas of the brain, all of which are tissues that are documented as being rich in DHA (13Tvrdik P. Westerberg R. Silve S. Asadi A. Jakobsson A. Cannon B. Loison G. Jacobsson A. Role of a new mammalian gene family in the biosynthesis of very long chain fatty acids and sphingolipids.J. Cell Biol. 2000; 149: 707-718Crossref PubMed Scopus (182) Google Scholar, 14Ohno Y. Suto S. Yamanaka M. Mizutani Y. Mitsutake S. Igarashi Y. Sassa T. Kihara A. ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.Proc. Natl. Acad. Sci. USA. 2010; 107: 18439-18444Crossref PubMed Scopus (240) Google Scholar). In contrast to testis and retina, PUFAs longer than C24 are almost undetectable in liver, mainly due to the low level of Elovl4 expression in this tissue, while PUFAs up to C22 are quite abundant within both the phospholipid and TG pools of hepatocytes (15Tikhonenko M. Lydic T.A. Wang Y. Chen W. Opreanu M. Sochacki A. McSorley K.M. Renis R.L. Kern T. Jump D.B. et al.Remodeling of retinal fatty acids in an animal model of diabetes: a decrease in long chain polyunsaturated fatty acids is associated with a decrease in fatty acid elongases Elovl2 and Elovl4.Diabetes. 2010; 59: 219-227Crossref PubMed Scopus (100) Google Scholar). As the first enzyme in the PUFA elongation chain, ELOVL5 activity is suggested to affect multiple pathways regulating hepatic lipid and carbohydrate composition in mammals (11Wang Y. Torres-Gonzalez M. Tripathy S. Botolin D. Christian B. Jump D.B. Elevated hepatic fatty acid elongase-5 activity affects multiple pathways controlling hepatic lipid and carbohydrate composition.J. Lipid Res. 2008; 49: 1538-1552Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar), while the role for ELOVL2 in liver is unknown. Our previous study, concerning the role of ELOVL2 in sperm maturation and male fertility, revealed that Elovl2−/− mice are infertile and heterozygote Elovl2+/− C57Bl/6 mice exhibit haploinsufficiency that gives rise to impaired spermatides in >99% of all male mice, which hindered us from obtaining homozygous Elovl2−/− mice (16Zadravec D. Tvrdik P. Guillou H. Haslam R. Kobayashi T. Napier J.A. Capecchi M.R. Jacobsson A. ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice.J. Lipid Res. 2011; 52: 245-255Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). To overcome this, we backcrossed Elovl2+/− females with 129S2/Sv males enabling the production of fertile Elovl2+/− males and subsequently generation of Elovl2−/− mice. In vitro data have suggested a role of ELOVL2 in the elongation of C20–C24 PUFAs. By using ELOVL2-ablated mice, we now show that the major in vivo substrates of ELOVL2 are C22:5n-3 and C22:4n-6. As a consequence, ELOVL2 completes the final elongation step in the synthesis of C22:5n-6 and C22:6n-3 in liver. Our data also reveal, for the first time, the physiological consequences of impaired ELOVL2 activity and endogenous DHA synthesis. The Elovl2-ablated mice have significantly levels of C22 PUFAs in that well with the levels in both the phospholipid and TG pools in liver. the mice show a in the of the omega-3 PUFAs and implying hepatic ELOVL2 as a in the of levels of DHA. As a consequence, an of hepatic sterol-regulatory element binding protein 1c (SREBP-1c), the Elovl2−/− mice show a to which is by dietary DHA Elovl2−/− mice were as (16Zadravec D. Tvrdik P. Guillou H. Haslam R. Kobayashi T. Napier J.A. Capecchi M.R. Jacobsson A. ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice.J. Lipid Res. 2011; 52: 245-255Abstract Full Text Full Text PDF PubMed Scopus (89) Google and backcrossed 129S2/Sv for were and a to male mice were and diet for a diet In to male mice were diet diet for by of diet the fatty acid composition of were and to As mice, from a heterozygote were and the as the Elovl2−/− mice. weight and were as in the the of the study, were with tissues were in and were with from the of the were by a of to a using a in the of to a with a of in and of in were and the in a of The the by et V. G. A. D. Lipid by for Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). to the were in were by of for to et B. N. fatty acid in human and phospholipid Lipid Res. 2010; Full Text Full Text PDF PubMed Scopus Google and were in to a with a of in the in a of and were to et V. G. A. D. Lipid by for Lipid Res. 2008; 49: Full Text Full Text PDF PubMed Scopus Google Scholar). were of and from Lipid were from with in from of liver using by of an P. J. B. of lipid by a PubMed Scopus Google Scholar). to a and a for using a of A and by A by from to in to being decreased to in 1 The to and using a the to the and the for of liver and the lipid from to and the lipid from to with all were in a of and to and by as H. P. P. J. Jakobsson M. of and fatty acid in Lipid 2013; 107: PubMed Scopus Google Scholar). In vivo using in to fat and To determine by as P. of energy in by Scopus Google Scholar). were to for 22 were and to in were 4 The the with with The were using and in a and production were energy to the and to the weight were in with and and by with and the using and cDNA were and of of the cDNA were with and and were in for were fatty acid 1 and 1 using the were to the gene of liver in and subsequently in 1 and and to for 1 in a The in 1 and and of 4 of the to for in a The as a protein using the of the protein from were by and to a in a The for 1 in with the in and and for 1 with Cell in and The with and and were using an and in an using and were with the role of ELOVL2 and PUFA synthesis in liver, we by in with the hepatic fatty acid composition in both the and TG pools in Elovl2-ablated mice and compared this with the fatty acid composition in an accumulation of the omega-6 fatty acids acid, and as well as the omega-3 fatty acids and in both liver and of mice compared with by a decrease in the levels of and respectively a role of ELOVL2 in the elongation process of C22 C24 PUFAs in the formation of DHA in liver the fatty acid in by the hepatic lipid liver as the major of DHA dietary has been that of the of PUFAs, especially DHA, lipid metabolism is via in the of the key lipogenic transcriptional As dietary supplementation with DHA has been shown to both hepatic and to positively influence the of the of DHA of target as and and de novo in mice J. R. S. W. M. P. et of dietary through of Full Text Full Text PDF PubMed Scopus Google Scholar, J. M. Clarke S.D. Polyunsaturated fatty acids hepatic sterol regulatory element-binding expression by Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M. feeding sterol regulatory element-binding protein 1 by of in liver. A for of lipogenic enzyme Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In with this, the Elovl2-ablated mice, which are in DHA, significantly hepatic levels of as well as protein As of in the of the downstream target for and were in the level of 2, and TG formation and fatty acid in the mice. are in with previous data showing a of by dietary DHA as well as with the mice that an of of levels of endogenously synthesized PUFAs longer than Y.A. Horton J.D. of ELOVL5 to fatty liver through of in mice.J. Lipid Res. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). of and its target has been proposed as a major in the development of hepatic steatosis due to of fatty acid and TG synthesis J.D. transcriptional of lipid Biol. PubMed Scopus Google Scholar). and Y.A. Horton J.D. of ELOVL5 to fatty liver through of in mice.J. Lipid Res. 2009; Full Text Full Text PDF PubMed Scopus Google that Elovl5 ablation and levels of PUFA to steatosis by impaired of Surprisingly, in hepatic lipogenic gene expression Elovl2−/− mice show accumulation of liver and from the we that Elovl2−/− liver significantly from hepatic and show of fat storage and steatosis significant in fat and energy Elovl2−/− mice and In we levels and and Elovl2−/− mice, TG and to Elovl2−/− mice and we a for the Elovl2-ablated to have energy than mice in the and the of the this in energy reversed the of the we the we that significantly the the mice are and have major implying that the for energy production than the mice we that a lipid to levels of fat accumulation in the Elovl2-ablated diet is to be of the that in as with insulin and fatty liver. In with this, has been that a diet the level of hepatic and induces hepatic steatosis via of J. R. S. W. M. P. et of dietary through of Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. E. J.M. of diet and sterol regulatory element-binding and the development of the 54: PubMed Scopus Google Scholar). To how Elovl2-ablated which have hepatic levels of to this of were a diet for the of diet the lipid composition in both liver and the in the PUFA Elovl2−/− and mice, diet In with the mice diet compared with diet to levels of both and protein in liver. the with diet levels in Elovl2−/− mice, significant in Elovl2−/− and mice However, Elovl2-ablated levels of protein the compared with and in contrast to the data from Elovl2−/− of by diet in in expression of the of lipogenic enzymes and in both and Elovl2−/− mice, an SREBP-1c-independent in the of Surprisingly, levels of by Elovl2−/− show of fatty liver and the TG levels were significantly than in mice which the that levels of DHA in mice are fatty liver. In with TG levels in liver, Elovl2−/− mice diet as weight in with mainly due to fat mass in the Elovl2−/− mice the first 4 of diet to be the the Elovl2−/− almost in weight fat in with in and for the in weight and feeding of Elovl2−/− mice be that of DHA within the diet to a significant in DHA accumulation with in mice To determine dietary DHA the weight and lipid accumulation of the Elovl2−/− mice, we a with a diet prior to a As in the in a significant in DHA levels in both liver and serum, which to a in both and Elovl2−/− mice. Surprisingly, levels of DHA and the hepatic level of protein and the lipogenic gene expression compared with a diet by DHA However, Elovl2−/− mice a diet weight and fat to the extent as implying an role for ELOVL2 and endogenous DHA synthesis in the of fat storage and energy in mammals. The DHA in a fatty liver the to the diet to a However, as previous data from that of Elovl2 in TG formation and lipid accumulation by an of target T. Zadravec D. Jacobsson A. ELOVL2 synthesis in and PubMed Scopus Google Scholar), we hepatic expression of and of its target genes. Elovl2−/− mice and However, a significant in as well as in in the Elovl2−/− mice, which DHA supplementation expression levels as the mice that omega-3 fatty in addition to through also lipid via an SREBP-1c-independent lipid storage and and By mice, we have shown that the ELOVL2 enzyme is for the elongation of PUFAs of the omega-6 family in testis PUFAs, which are essential precursors for elongation by ELOVL4 that are for sperm formation and fertility in mice (16Zadravec D. Tvrdik P. Guillou H. Haslam R. Kobayashi T. Napier J.A. Capecchi M.R. Jacobsson A. ELOVL2 controls the level of n-6 28:5 and 30:5 fatty acids in testis, a prerequisite for male fertility and sperm maturation in mice.J. Lipid Res. 2011; 52: 245-255Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar). As liver we show in the that the function of hepatic ELOVL2 is elongation of 24-carbon PUFAs for the formation of DPAn-6 and in the omega-3 PUFA DHA. as liver is of the tissues with the Elovl2 expression a in levels of DHA in Elovl2−/− mice that liver is the major of DHA dietary The data also that the expressed elongase ELOVL5, in with the desaturases and 2, are the major enzymes involved in the formation of PUFAs up to 22 carbons in vivo. animal in the PUFA by ablation of ELOVL5 Y.A. Horton J.D. of ELOVL5 to fatty liver through of in mice.J. Lipid Res. 2009; Full Text Full Text PDF PubMed Scopus Google FADS2 W. B. B. E. M. S. et deficiency the role of and fatty J. 2008; PubMed Scopus Google Scholar, M. P. Y. M. et of FADS2 gene in mice male and and Lipid Res. 2009; Full Text Full Text PDF PubMed Scopus Google also levels of DPAn-6 and DHA. However, as and elongation of both Elovl5 and to decreased of PUFAs, as and the levels of which were substantially in the the in the The animal model by et M. P. Y. M. et of FADS2 gene in mice male and and Lipid Res. 2009; Full Text Full Text PDF PubMed Scopus Google by as well as that be by dietary supplementation of which also the of this in animal In et W. B. B. E. M. S. et deficiency the role of and fatty J. 2008; PubMed Scopus Google the and in lipid and carbohydrate metabolism of which be due for in the dietary of in the of Elovl5 revealed a and DHA deficiency in liver and of via an that hepatic steatosis in the mice. In the Elovl2−/− mice, DHA levels and hepatic fatty liver an that overcome by diet A for the in lipid metabolism the is the levels of substrates and in the Elovl2−/− mice compared with the The level of PUFAs, especially and C22 significantly in the Elovl2−/− mice compared with both and the mice. as well as DHA, has been shown to be a in and of including insulin resistance and hepatic steatosis A. Horrillo R. Ferré N. Gronert K. Dong B. Morán-Salvador E. Titos E. Martínez-Clemente M. López-Parra M. Arroyo V. et al.Obesity-induced insulin resistance and hepatic steatosis are alleviated by omega-3 fatty acids: a role for resolvins and protectins.FASEB J. 2009; 23: 1946-1957Crossref PubMed Scopus (470) Google Scholar, 4Oosterveer M.H. van Dijk T.H. Tietge U.J. Boer T. Havinga R. Stellaard F. Groen A.K. Kuipers F. Reijngoud D.J. High fat feeding induces hepatic fatty acid elongation in mice.PLoS ONE. 2009; 4: e6066Crossref PubMed Scopus (117) Google Scholar, A. H. T. M. Nakakuki M. K. M. T. Y. of acid in diet-induced of hepatic 2010; 59: PubMed Scopus Google Scholar, Y. Wang J. T. Wang Y. phospholipid insulin resistance and lipid metabolism in 2013; PubMed Scopus Google Scholar). is the that is the major the in the Elovl2−/− mice is in addition to the of Elovl2 in endogenous DHA data dietary supplementation of DHA in Elovl2−/− mice also new the physiological role of dietary a role of diet supplementation with DHA indicate hepatic as the major target in the of hepatic and development of fatty liver J. F. Wang Y. R. M. D. A. et dietary n-3 PUFA and in the rat model of the J. Nutr. 2011; PubMed Scopus Google Scholar, A. E. N. et n-3 polyunsaturated fatty acid steatosis and insulin resistance in of ONE. 2011; PubMed Scopus Google Scholar). In the study, we show that of the formation of endogenous DHA positively affects hepatic However, this be reversed by a with dietary DHA. of Elovl2 lipid storage in to a diet of DHA levels in liver and of Elovl2−/− as a of dietary the of fat with previous in Elovl2 in fat the data that omega-3 fatty in addition to through also lipid via an SREBP-1c-independent lipid storage and T. Zadravec D. Jacobsson A. ELOVL2 synthesis in and PubMed Scopus Google Scholar, E.G. and as and Biophys. PubMed Scopus Google Scholar, D. J.D. S. Y. M. M. the acid and development of insulin resistance in mice.J. Lipid Res. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). 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J.M. deficiency mice from and hepatic Full Text Full Text PDF PubMed Scopus Google that that mice were from by were resistant to that hepatic enzyme a role in the to diet in Elovl2−/− mice. have the role of the ELOVL2 enzyme in the formation of DHA as well as in fat accumulation in hepatocytes liver The of ELOVL2 this is including fatty acid and The data also show that impaired fat due to endogenous DHA synthesis to a certain be by dietary relatively that impaired Elovl2 expression is highly with lipid metabolism and in T. J. A. J.M. J.M. A. S. A. D. et of polyunsaturated fatty acids in the 2009; PubMed Scopus Google Scholar, T. G. W. R. E. G. et of in human 2010; PubMed Scopus Google Scholar). Elovl2 activity a target for the of DHA deficiency in mammals. The R. H. and S. for with acid docosapentaenoic acid elongation of very long-chain fatty acid fatty acid fatty acid 1 energy 1 sterol-regulatory element binding protein 1c