Dual Promoter Structure of Mouse and Human Fatty Acid Translocase/CD36 Genes and Unique Transcriptional Activation by Peroxisome Proliferator-activated Receptor α and γ Ligands

Fatty acid translocase (FAT)/CD36 is a glycoprotein involved in multiple membrane functions including uptake of long-chain fatty acids and oxidized low density lipoprotein. In mice, expression of the gene is regulated by peroxisome proliferator-activated receptor (PPAR) α in the liver and by PPARγ in the adipose tissues (Motojima, K., Passilly, P. P., Peters, J. M., Gonzalez, F. J., and Latruffe, N. (1998) J. Biol. Chem. 273, 16710–16714). However, the time course of PPARα ligand-induced expression of FAT/CD36 in the liver, and also in the cultured hepatoma cells, is significantly slower than those of other PPARα target genes. To study the molecular mechanism of the slow transcriptional activation of the gene by a PPAR ligand, we first cloned the 5′ ends of the mRNA and then the mouse gene promoter region from a genomic bacterial artificial chromosome library. Sequencing analyses showed that transcription of the gene starts at two initiation sites 16 kb apart and splicing occurs alternatively, producing at least three mRNA species with different 5′-noncoding regions. The PPARα ligand-responsive promoter in the liver was identified as the new upstream promoter where we found several possible binding sites for lipid metabolism-related transcriptional factors but not for PPAR. Neither promoter responded to a PPARα ligand in thein vitro or in vivo reporter assays using cultured hepatoma cells and the liver of living mice. We also have cloned the human FAT/CD36 gene from a bacterial artificial chromosome library and identified a new independent promoter that is located 13 kb upstream of the previously reported promoter. Only the upstream promoter responded to PPARα and PPARγ ligands in a cell type-specific manner. The absence of PPRE in the responding upstream promoter region, the delayed activation by the ligand, and the results of the reporter assays all suggested that transcriptional activation of the FAT/CD36 gene by PPAR ligands is indirectly dependent on PPAR. Fatty acid translocase (FAT)/CD36 is a glycoprotein involved in multiple membrane functions including uptake of long-chain fatty acids and oxidized low density lipoprotein. In mice, expression of the gene is regulated by peroxisome proliferator-activated receptor (PPAR) α in the liver and by PPARγ in the adipose tissues (Motojima, K., Passilly, P. P., Peters, J. M., Gonzalez, F. J., and Latruffe, N. (1998) J. Biol. Chem. 273, 16710–16714). However, the time course of PPARα ligand-induced expression of FAT/CD36 in the liver, and also in the cultured hepatoma cells, is significantly slower than those of other PPARα target genes. To study the molecular mechanism of the slow transcriptional activation of the gene by a PPAR ligand, we first cloned the 5′ ends of the mRNA and then the mouse gene promoter region from a genomic bacterial artificial chromosome library. Sequencing analyses showed that transcription of the gene starts at two initiation sites 16 kb apart and splicing occurs alternatively, producing at least three mRNA species with different 5′-noncoding regions. The PPARα ligand-responsive promoter in the liver was identified as the new upstream promoter where we found several possible binding sites for lipid metabolism-related transcriptional factors but not for PPAR. Neither promoter responded to a PPARα ligand in thein vitro or in vivo reporter assays using cultured hepatoma cells and the liver of living mice. We also have cloned the human FAT/CD36 gene from a bacterial artificial chromosome library and identified a new independent promoter that is located 13 kb upstream of the previously reported promoter. Only the upstream promoter responded to PPARα and PPARγ ligands in a cell type-specific manner. The absence of PPRE in the responding upstream promoter region, the delayed activation by the ligand, and the results of the reporter assays all suggested that transcriptional activation of the FAT/CD36 gene by PPAR ligands is indirectly dependent on PPAR. fatty acid translocase bacterial artificial chromosome acyl-CoA oxidase peroxisome proliferator-activated receptor peroxisome proliferator-activated receptor-responsive element retinoid X receptor sterol-responsive element reverse transcription hydratase-dehydrogenase liver fatty acid-binding protein long-chain acyl-CoA synthetase apolipoprotein FAT1/CD36 is a glycosylated membrane protein normally expressed on the surface of monocyte-macrophage lineage cells (1Talle M.A. Rao P.E. Westber E. Allegar N. Makowski M. Mittler R.S. Goldstein G. Cell. Immunol. 1983; 28: 83-99Crossref Scopus (130) Google Scholar), platelets (2Li Y.S. Shyy Y.J. Wright J.G. Valente A.J. Cornhill J.F. Kolattukudy P.E. Mol. Cell. Biochem. 1993; 26: 61-68Crossref Scopus (71) Google Scholar), microvascular endothelial cells (3Greenwalt D.E. Lipsky R.H. Ockenhouse C.F. Ikeda H. Tandon H.H. Jamieson G.A. Blood. 1992; 80: 1105-1115Crossref PubMed Google Scholar), and adipocytes (4Abumrad N.A. Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar). FAT was identified as a fatty acid translocase abundantly expressed on differentiated adipocytes (4Abumrad N.A. Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar), and CD36 was identified as an oxidized low density protein receptor that does not recognize acetylated low density lipoprotein on macrophages (5Endemann G. Stanton L.W. Madden K.S. Bryant C.M. White R.T. Protter A.A. J. Biol. Chem. 1993; 268: 11811-11816Abstract Full Text PDF PubMed Google Scholar). Sequence comparison revealed that the two independently identified glycoproteins are the same. FAT/CD36 has been shown also to be involved in foam cell formation in early atherosclerosis (6Nagy L. Tontonoz P. Alvalez J.G.A. Chen H. Evans R.M. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1594) Google Scholar, 7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar), in apoptosis (8Ren Y. Silverstein R.L. Allen J. Savill J. J. Exp. Med. 1995; 181: 1857-1862Crossref PubMed Scopus (350) Google Scholar), and in angiogenesis (9Dawson D.W. Pearce S.F. Zhong R. Silverstein R.L. Frazier W.A. Bouck N.P. J. Cell Biol. 1997; 138: 707-717Crossref PubMed Scopus (547) Google Scholar) by recognizing a variety of ligands such as long-chain fatty acid (10Abumrad N. Harmon C. Ibrahimi A. J. 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Full Text Full Text PDF PubMed Scopus Google Scholar). However, not all the results of and human are The reported of and of human are the fatty acid and the in Y. N. Full Text Full Text PDF PubMed Google Scholar). results that other in to FAT/CD36 are also with the and the of several but also that FAT/CD36 is a fatty acid in adipocytes and was by the that a in human long-chain fatty acid uptake is by FAT/CD36 F. Y. J. Lipid Res. Full Text Full Text PDF PubMed Google Scholar). of the FAT/CD36 gene be regulated to functions in cell FAT/CD36 expression has been on macrophages and is to be regulated by K.S. H. J. A. 1992; PubMed Scopus Google Scholar, Pearce S.F. Silverstein R.L. Biol. PubMed Scopus Google Scholar) and by ligands of the peroxisome proliferator-activated receptor (PPAR) (6Nagy L. Tontonoz P. Alvalez J.G.A. Chen H. Evans R.M. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1594) Google Scholar, 7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar). We the of PPARα and PPARγ ligands on the expression of FAT/CD36 mRNA in mouse tissues and showed that the mRNA is by PPARα in the liver and by PPARγ ligands in adipose tissues N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The time course of mRNA by a PPARα ligand in the liver is significantly slower than those of other PPARα target the of PPARα in transcriptional activation was of in N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). suggested that the mechanism of transcriptional activation is not on the FAT/CD36 gene as on other PPARα target genes. However, on the PPARγ ligand-induced expression of the human FAT/CD36 gene in showed that the human gene promoter PPARγ and is by ligands in a (6Nagy L. Tontonoz P. Alvalez J.G.A. Chen H. Evans R.M. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1594) Google Scholar). The PPRE identified by (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar) is not Tontonoz (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar) showed to and the by the receptor and ligand in cultured cells using the of the promoter was not as as that of the gene in (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar). not the of the human FAT/CD36 gene the of the gene was not we to the of the FAT/CD36 of mouse and then of The results by of the mouse and human FAT/CD36 that the promoter previously is the promoter that does not to PPAR have independent promoter located indirectly to the acid was from and was from the at and as Y. PubMed Scopus Google Scholar). reporter and reporter from and from and a from and FAT/CD36 was from a and with and a or that for In vivo of the liver of was as K., K., K., and Mol. Cell. Biochem. in of was and at at using an a of or a for The of the liver was and the cells, a of hepatoma cells, cultured in the reported previously N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). cells and human and from Y. cultured in and cultured in was as previously Y. PubMed Scopus Google Scholar). PPAR ligand was to the as a in by The of the ligands The in the cell and reporter was in with for cells and for cells to the we as an and reporter The cells cultured in in the or absence of PPAR The using the to the was from the mouse liver and cultured cells by the acid P. N. Biochem. 1987; PubMed Scopus Google Scholar). was as previously N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar), that was in at for the and with an at a was The to of the mouse FAT/CD36 mRNA by of using the or the cloned and by The by of the and of other as have been previously N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). the mouse mRNA was from the liver, and of a or that for as The from of using and reverse The FAT/CD36 by of using the of or and the human mRNA was from cells and cells with PPAR ligands and the from of using or and reverse The FAT/CD36 by of using the of an or and an by and with the cloned of with to ends and for The the 5′ of mouse and human FAT/CD36 by a N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The first was from of from the of for or from of from The was three and with of and at for or The of the was by using and a mouse to of the (4Abumrad N.A. Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar) or a human to the in the Y. Lipsky R.H. 1993; PubMed Scopus Google Scholar, Y. Lipsky R.H. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar) in was to the to the ends of the The using a and cloned of The on and to FAT/CD36 possible new promoter of the mouse FAT/CD36 gene was by using a mouse to the The of the was from the new a using the as and the with the the on and cloned the of the previously reported promoter region was cloned by using the (4Abumrad N.A. Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google a possible new and the previously reported promoter of the human FAT/CD36 the as was of the from the new as and the M.A. J. Biol. Chem. Full Text PDF PubMed Google the on and cloned the of density of genomic library using the mouse for the region of FAT/CD36 (4Abumrad N.A. Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar, N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) the by the and by to a a promoter the human genomic density of genomic library using the by as the by the and by to a a promoter of the a of a at a using was for the and the by a We have shown previously that the PPARα ligand expression of FAT/CD36 mRNA in the mouse We also a time of the mRNA than other PPARα target gene N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). To the delayed of FAT/CD36 mRNA by the ligand, we a study to the in the of FAT/CD36 and PPARα such as liver fatty acid-binding protein and long-chain acyl-CoA synthetase N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) and of all FAT/CD36 mRNA in the mouse liver a time of a as by a also the of the in a and the for several In the FAT/CD36 mRNA at a low for and the at is that the PPARα ligand-induced expression of FAT/CD36 mRNA was significantly delayed as with other To the delayed of FAT/CD36 mRNA by the PPARα ligand in the liver was by of the ligand-induced in other we in the of the in the hepatoma cells The for the such as and by the of a of FAT/CD36 mRNA was a of the mechanism of the transcriptional activation of the FAT/CD36 gene is not the as that of other PPARα target genes. of the in vivo delayed in the cultured cells that or in tissues not an in the To study the molecular mechanism of the delayed of mouse FAT/CD36 gene expression by a PPARα ligand, we the promoter of the of the 5′ of the mRNA from the liver of by the a a 5′ different from the of the 5′ showed with a FAT/CD36 M. E. 1997; PubMed Scopus Google Scholar) that the was not a but was from the first and that has To the of the mouse FAT/CD36 we first cloned the previously reported promoter and the possible upstream of the new using a the cloned genomic by a mouse genomic library was using the for the region (4Abumrad N.A. Maghrabi M.R. Amri E.Z. Lopez E. Grimaldi P.A. J. Biol. Chem. 1993; 268: 17665-17668Abstract Full Text PDF PubMed Google Scholar). The from by for the of the new and the FAT/CD36 that on the also the two possible promoter results the that the new was from a different from the FAT/CD36 gene by a was and by and as in The of the from a with those of the and the the two was by as 16 To that new and the from the we by all the shown in in the and or and of the at least three mRNA species with different 5′-noncoding identified by and results that the mouse FAT/CD36 gene has two and independent first and the new first is located 16 kb upstream from that previously (5Endemann G. Stanton L.W. Madden K.S. Bryant C.M. White R.T. Protter A.A. J. Biol. Chem. 1993; 268: 11811-11816Abstract Full Text PDF PubMed Google Scholar). of we in and found a genomic to the upstream promoter of the mouse FAT/CD36 of the revealed that several in the from to to the transcriptional are In than of the in the from to are the two the of the FAT/CD36 genes. To the promoter of the FAT/CD36 gene found in the mouse is in the human we first the 5′ of the FAT/CD36 mRNA by the The from the from cells was by using a to the of M.A. J. Biol. Chem. Full Text PDF PubMed Google Scholar) and in Sequencing of revealed that the of and a new on new we cloned the possible new promoter using a and then the genomic from the genomic library as for the mouse The results of and of kb the new and kb the previously reported first are in with the mouse The human FAT/CD36 gene has two by a of 13 as by results that the promoter is at least in mouse and of the of we found in the of the of the two of showed that the promoter was to that in the and that of the promoter was The of the a region of in the of the first with The the two on the is kb of the 13 kb suggested by also that the two promoter from a gene but not from two genes. analyses of the of FAT/CD36 mRNA the for the region as and not the two first To promoter responded to PPARα and PPARγ we for and the for We first of from the liver and of a a PPARα ligand, for to using The of FAT/CD36 mRNA by the region in the liver and that of the mRNA by the in the liver and was not by the to the of the FAT/CD36 gene to PPARγ ligands was using the from cells with PPARα or PPARγ ligands FAT/CD36 mRNA as a was by PPARα and PPARγ using the revealed that the mRNA the of was as we not the mRNA the of with the by of the of the with low of we to that the mRNA was not by the PPAR of the mRNA from the liver, and of a or that showed that the FAT/CD36 mRNA species in the liver but not and that of in the results that of the FAT/CD36 gene are in the liver, and but the promoter to at least in the liver and that a different mechanism is in the has been that the human FAT/CD36 mRNA is by PPARγ ligands in A. H.H. Krieger M. PubMed Scopus Google Scholar). The mechanism (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar) was on the and we found a promoter in the human gene as in that of the To promoter to PPARγ ligands and the of PPARα we the expression of FAT/CD36 at the protein and mRNA We first the of PPAR ligands on the expression of FAT/CD36 mRNA in two human cell and by from the cells with the PPARα ligand or PPARγ ligand was with the FAT/CD36 for the region was in the from cells of the mRNA by PPARα or PPARγ ligand was in We the cell surface expression of FAT/CD36 protein in cells by using a to FAT/CD36 and in of FAT/CD36 was on cells with the PPARα or PPARγ ligand PPARα and PPARγ in of FAT/CD36 mRNA and protein in the human cell To promoter to PPAR we using the and a as shown in we cloned the with a new 5′ from cells, we from and In cells, of the was to the mRNA but was using the for in of the mRNA by was in cells with that the promoter is but not to PPARα ligands in cells the In cells, in and the promoter responded to PPARα and PPARγ ligands To the two of the mouse FAT/CD36 gene are independent and the promoter to PPAR ligands as in the a reporter of the in cells and in cells was We the promoter from a and a of promoter to the in vitro promoter N. 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PubMed Scopus Google Scholar). of the two of of the mouse gene than those of promoter in and cells, that the two are independently in of the ligands for PPARα or showed on the promoter of in or cells, the ligands significantly the artificial PPRE promoter in the We the PPAR ligand of the promoter by an in vivo gene using the of living but ligand-induced transcriptional activation of the reporter gene was not we that the two cloned promoter of the mouse FAT/CD36 gene not for transcriptional activation by the and We also to the two promoter of the human FAT/CD36 gene by a reporter using the PPAR ligand-responsive cell However, an we that of the human gene independently in cells of the of and expression of the reporter gene was low not of the be for of PPAR ligand of the two in FAT/CD36 is a receptor for the uptake of oxidized low density lipoprotein in macrophages and a for long-chain fatty acids in the and is to a of including atherosclerosis and of expression is an but have been on the promoter of the FAT/CD36 The results that the mouse and human have two independent and the identified upstream to the PPAR not a of FAT/CD36 gene we that the mRNA is by PPARα ligands a in the liver and hepatoma cells N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, 1997; 79: PubMed Scopus Google Scholar, Cell 1993; PubMed Scopus Google Scholar). The Cell 1993; PubMed Scopus Google Scholar) the in the time course of but the mechanism of PPARγ ligand-induced expression of the human FAT/CD36 gene in was previously by a (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar). the that be by in species cell not be we the to the human as The as PPRE in study is not the and the promoter does not an PPRE by C. A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). binding of the and PPARγ in not from but from cells not that the in the promoter the receptor in was reported that binding of transcription factors and binding and Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). the reported of the with the and ligands to that was low to the of the gene (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar). The of the promoter of the FAT/CD36 gene be in two multiple independent possible to transcription of the gene by in a cell type-specific multiple functions in the in the region the of the mRNA the of was that the region of the human FAT/CD36 mRNA a with and is for of FAT/CD36 E. A. N. C. H. A.S. Med. PubMed Scopus Google Scholar). We the in the of the mouse and human FAT/CD36 regions. The first upstream was shown to be for to was in the using the upstream promoter. be to the mechanism to independently FAT/CD36 expression at the of the mRNA by a and at the transcriptional of the upstream by a PPAR However, the mouse not the mechanism as the human gene the in the mouse by the are not to those in The of the of the FAT/CD36 The mouse FAT/CD36 mRNA is by PPAR ligands in a PPAR and N. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). The activation is not the as that of PPAR target genes. the time course of the is significantly delayed as with other The gene has a promoter in a and PPRE was not a reporter using the two cloned of the mouse gene not the in vivo results suggested that transcriptional activation of the mouse gene by the PPARα at least in the liver, is indirectly dependent on the human FAT/CD36 we also found that the previously promoter does not to PPAR in to the results (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar). of the mRNA by the PPARγ ligands was and by the that the PPARα ligands are also We that the of reporter and a assays to the to the mechanism by activation of the promoter are not as that the in the promoter PPARγ but not PPARα is to that the mRNA was by PPARα and PPARγ ligands at that showed PPAR We showed that the promoter of the human gene responded to PPAR ligands by of the 5′ of the We not a PPRE C. A. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) in the promoter of the human gene as in the mouse results of of the and expression of the mouse and human we that the expression of the human FAT/CD36 gene is indirectly regulated by the the mechanism is the of the and of the promoter found in study be of an mechanism as that be dependent on the cell The of PPARγ and FAT/CD36 in have the of the of PPARγ ligands on the expression of FAT/CD36 in (6Nagy L. Tontonoz P. Alvalez J.G.A. Chen H. Evans R.M. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1594) Google Scholar, 7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar), and the have been shown to be of PPARγ was from several F. R.M. Med. PubMed Scopus Google Scholar, A. Nagy L. Tontonoz P. Evans R.M. Med. PubMed Scopus Google Scholar, G. E. A. M. N. Med. PubMed Scopus Google Scholar, J. Clin. Invest. PubMed Scopus Google Scholar), the expression of FAT/CD36 is to be involved in of foam cell formation (7Tontonoz P. Nagy L. Alvarez J.G.A. Thomazy V.A. Evans R.M. Cell. 1998; 93: 241-252Abstract Full Text Full Text PDF PubMed Scopus (1613) Google Scholar). The of the PPARγ ligands on the expression of FAT/CD36 and receptor for oxidized low density lipoprotein P. C. Krieger M. A. PubMed Scopus Google Scholar), is also as are on macrophages by F. R.M. Med. 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PubMed Scopus Google Scholar). J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) showed that the expression of PPARα in cells a but not all of the in the liver with to the ligand in human results suggested that factors in to PPAR and in the PPAR transcriptional activation of several genes. be not to the by but to the PPAR