Stearoyl-CoA Desaturase Is Involved in the Control of Proliferation,Anchorage-independent Growth, and Survival in Human TransformedCells

Abstract

Saturated and monounsaturated fatty acids are the most abundant fatty acidspecies in mammalian organisms, and their distribution is regulated bystearoyl-CoA desaturase, the enzyme that converts saturated intomonounsaturated fatty acids. A positive correlation between highmonounsaturated fatty acid levels and neoplastic transformation has beenreported, but little is still known about the regulation of stearoyl-CoAdesaturase in cell proliferation and apoptosis, as well as in cancerdevelopment. Here we report that simian virus 40-transformed human lungfibroblasts bearing a knockdown of human stearoyl-CoA desaturase by stableantisense cDNA transfection (hSCDas cells) showed a considerablereduction in monounsaturated fatty acids, cholesterol, and phospholipidsynthesis, compared with empty vector transfected-simian virus 40 cell line(control cells). hSCDas cells also exhibited high cellular levels ofsaturated free fatty acids and triacylglycerol. Interestingly, stearoyl-CoAdesaturase-depleted cells exhibited a dramatic decrease in proliferation rateand abolition of anchorage-independent growth. Prolonged exposure to exogenousoleic acid did not reverse either the slower proliferation or loss ofanchorage-independent growth of hSCDas cells, suggesting thatendogenous synthesis of monounsaturated fatty acids is essential for rapidcell replication and invasiveness, two hallmarks of neoplastic transformation.Moreover, apoptosis was increased in hSCDas cells in aceramide-independent manner. Finally, stearoyl-CoA desaturase-deficient cellswere more sensitive to palmitic acid-induced apoptosis compared with controlcells. Our data suggest that, by globally regulating lipid metabolism,stearoyl-CoA desaturase activity modulates cell proliferation and survival andemphasize the important role of endogenously synthesized monounsaturated fattyacids in sustaining the neoplastic phenotype of transformed cells. Saturated and monounsaturated fatty acids are the most abundant fatty acidspecies in mammalian organisms, and their distribution is regulated bystearoyl-CoA desaturase, the enzyme that converts saturated intomonounsaturated fatty acids. A positive correlation between highmonounsaturated fatty acid levels and neoplastic transformation has beenreported, but little is still known about the regulation of stearoyl-CoAdesaturase in cell proliferation and apoptosis, as well as in cancerdevelopment. Here we report that simian virus 40-transformed human lungfibroblasts bearing a knockdown of human stearoyl-CoA desaturase by stableantisense cDNA transfection (hSCDas cells) showed a considerablereduction in monounsaturated fatty acids, cholesterol, and phospholipidsynthesis, compared with empty vector transfected-simian virus 40 cell line(control cells). hSCDas cells also exhibited high cellular levels ofsaturated free fatty acids and triacylglycerol. Interestingly, stearoyl-CoAdesaturase-depleted cells exhibited a dramatic decrease in proliferation rateand abolition of anchorage-independent growth. Prolonged exposure to exogenousoleic acid did not reverse either the slower proliferation or loss ofanchorage-independent growth of hSCDas cells, suggesting thatendogenous synthesis of monounsaturated fatty acids is essential for rapidcell replication and invasiveness, two hallmarks of neoplastic transformation.Moreover, apoptosis was increased in hSCDas cells in aceramide-independent manner. Finally, stearoyl-CoA desaturase-deficient cellswere more sensitive to palmitic acid-induced apoptosis compared with controlcells. Our data suggest that, by globally regulating lipid metabolism,stearoyl-CoA desaturase activity modulates cell proliferation and survival andemphasize the important role of endogenously synthesized monounsaturated fattyacids in sustaining the neoplastic phenotype of transformed cells. Saturated (SFA) 1The abbreviations used are: SFA, saturated fatty acid; MUFA,monounsaturated fatty acids; SCD, stearoyl-CoA desaturase; TAG,:triacylglycerol; CE, cholesterol ester; FFA, unesterified fatty acid; hSCD,human stearoyl-CoA desaturase; FBS, fetal bovine serum; BSA, bovine serumalbumin; MEM, minimal essential medium.and monounsaturated (MUFA) fatty acids are the most abundant fatty acidspresent in mammalian organisms. As building blocks of phospholipids,triacylglycerols (TAGs), and cholesteryl esters (CEs), fatty acids arefundamental constituents of membranes, vital stores of metabolic energy, andrelevant mediators/signals that regulate major cellular activities. Becausechanging levels of SFA and MUFA can influence a broad spectrum of cellularfunctions, the content and distribution of SFA and MUFA within the cell mustbe tightly controlled. One key regulator of fatty acid composition isstearoyl-CoA desaturase (SCD), the endoplasmic reticulum-resident enzyme thatcatalyzes the introduction of the first double bond in thecis-Δ9 position of several saturated fatty acyl-CoAs,principally palmitoyl-CoA and stearoyl-CoA, to render palmitoleyl- andoleyl-CoA (1Enoch H.G. Catalá A. Strittmatter P. J. Biol. Chem. 1976; 251: 5095-5103Abstract Full Text PDF PubMed Google Scholar). The presence of SCD has been described in a wide variety of organisms(2Sperling P. Ternes P. Zank T.K. Heinz E. Prost. Leukotr. Essential FattyAcids. 2003; 68: 73-96Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). Among the best studiedmammalian models, rodents have four SCD isoforms (SCD1–4) expressed in atissue-specific manner (3Ntambi J.M. Miyazaki M. Prog. Lipid Res. 2004; 43: 91-104Crossref PubMed Scopus (552) Google Scholar). SCDexpression and activity are regulated by a large number of factors, includingdietary cholesterol and fatty acids, several hormones, and growth factors(4Ntambi J.M. J. LipidRes. 1999; 40: 1549-1558Abstract Full Text Full Text PDF PubMed Google Scholar). Most of these studies havebeen done using rodent models, and little is known about human SCD. Twoisoforms of SCD (SCD and ACOD4) have been described for humans, bothexhibiting ∼85% homology with murine SCD1(5Zhang L. Ge L. Parimoo S. Stenn K. Prouty S.M. Biochem. J. 1999; 340: 255-264Crossref PubMed Scopus (204) Google Scholar,6Beiraghi S. Zhou M. Talmadge C.B. Went-Sumegi N. Davis J.R. Huang D. Saal H. Seemayer T.A. Sumegi J. Gene (Amst.). 2003; 309: 11-21Crossref PubMed Scopus (65) Google Scholar). ACOD4 is almost exclusivelyexpressed in fetal brain, with little or no detectable expression in adulttissues (6Beiraghi S. Zhou M. Talmadge C.B. Went-Sumegi N. Davis J.R. Huang D. Saal H. Seemayer T.A. Sumegi J. Gene (Amst.). 2003; 309: 11-21Crossref PubMed Scopus (65) Google Scholar). The SCD gene isubiquitously expressed, although the overall level of expression differs amongtissues, with high levels in brain, liver, heart, and lung(5Zhang L. Ge L. Parimoo S. Stenn K. Prouty S.M. Biochem. J. 1999; 340: 255-264Crossref PubMed Scopus (204) Google Scholar). Because the lipid products of SCD are used for modulating membranestructure (7Sun Y. Hao M. Luo Y. Liang C.P. Silver D.L. Cheng C. Maxfield F.R. Tall A.R. J. Biol.Chem. 2003; 278: 5813-5820Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar,8Hao M. Mukherjee S. Sun Y. Maxfield F.R. J. Biol. Chem. 2004; 279: 14171-14178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar) and/or energy metabolism(3Ntambi J.M. Miyazaki M. Prog. Lipid Res. 2004; 43: 91-104Crossref PubMed Scopus (552) Google Scholar), SCD has been suggested toplay a key role in cell proliferation and in lipid-mediated cytotoxicity. Inthis regard, it has been observed that SCD is a target of growth factors andhormones that regulate key cell cycle events. Retinoic acid and transforminggrowth factor-β are reported to regulate SCD expression in a number ofuntransformed human cell types(9Samuel W. Kutty R.K. Nagineni S. Gordon J.S. Prouty S.M. Chandraratna R.A.S. Wiggert B. J.Biol. Chem. 2001; 276: 28744-28750Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,10Samuel W. Nagineni C.N. Kutty R.K. Parks W.T. Gordon J.S. Prouty S.M. Hooks J.J. Wiggert B. J. Biol. Chem. 2002; 277: 59-66Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar). Very recently, it wasdemonstrated that platelet-derived growth factor and fibroblast growth factorsFGF-2 and FGF-4 up-regulate SCD expression in human fibroblasts through theactivation of sterol regulatory element-binding protein 1 (SREBP-1) byphosphatidylinositol 3-kinase(11Demoulin J.B. Ericsson J. Kallin A. Rorsman C. Ronnstrand L. Heldin C.H. J. Biol.Chem. 2004; 279: 35392-35402Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). In this work, theactivation of SCD by growth factors was paralleled by an increase in thesynthesis of phospholipids and cholesterol, supporting the idea that MUFAsynthesis is an integral part of the program of membrane synthesis. SCD has arole in lipid-mediated apoptosis, because it has been shown thatoverexpression of SCD1 in Chinese hamster ovary cells protects against thecytotoxic effects of excess SFA(12Listenberger L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer S. A. 2003; PubMed Scopus Google Scholar). A between SCD activity and cell proliferation has also expression level of SCD was in and in J. C.B. J. PubMed Scopus Google Scholar), as well as in 2001; PubMed Scopus Google Scholar). we reported that human cells) a fatty acid synthesis and increased protein and activity levels of SCD with to cell and this in an increased and a more cell membrane N. J.M. PubMed Scopus Google Scholar). Because synthesis with a replication C. J.Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar), the increased MUFA in these cells the high for this fatty acid membrane lipid synthesis. that SCD, by modulating the levels of SFA and a regulator of essential of lipid lipid synthesis and as well as fatty acids. As SCD activity to and/or increased cell this a of SCD gene expression in human cells. this human because this cell several and that these cells to the effects of SCD in lipid well as in cell and cell SCD protein and activity levels are to a high MUFA synthesis and N. J.M. PubMed Scopus Google As a human cells the SCD in not the L. Ge L. Parimoo S. Stenn K. Prouty S.M. Biochem. J. 1999; 340: 255-264Crossref PubMed Scopus (204) Google Scholar,6Beiraghi S. Zhou M. Talmadge C.B. Went-Sumegi N. Davis J.R. Huang D. Saal H. Seemayer T.A. Sumegi J. Gene (Amst.). 2003; 309: 11-21Crossref PubMed Scopus (65) Google L. Ge L. Stenn K. Prouty S.M. Biochem. J. 2001; PubMed Scopus Google Scholar), increase of SCD in cell these the of a well known for transformation the of and a that is most human M. M. H. P. Res. 1999; PubMed Scopus Google S. M. M. 2002; Google Scholar). In the we that the knockdown of SCD by a cDNA in human neoplastic MUFA and synthesis and the unesterified fatty acids and to a slower of cell a loss ofanchorage-independent and of cells that levels of SCD are to the effects of palmitic Because phenotype of cells was not by the endogenously synthesized MUFA essential to cellular lipid this to suggest is important in the of cells, of of human the The human SCD cDNA to of was a of M. W. and of cell and fetal bovine was and acid lipid was and was cells as well as the cell in with with FBS, acids, and and SCD in human was a vector in an and The cells using the cells in for cell using vector was these cells the cell was described N. J.M. PubMed Scopus Google or used as Lipid and the with two of 1 1 of and of the as described by and Scholar). of SCD cells with acid in for the of the cell as cellular and acids with in for The esters by the of and J.R. A. 2001; PubMed Scopus Google Scholar), using a of by acid and in to the acid by as well as by lipid with the and with The level of acid activity of acid to cellular protein cells for either with acid or acid in with the the was and with in to the cell Lipid was Lipid and of of and by and C. J.Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). lipid with as lipid in a and the in to the lipid and in a The in lipid was activity of and to cellular the of fatty acid composition of phospholipids and by as and fatty acid esters lipid as described esters of fatty acids by in a with a with an by of their with of and distribution was of was using of acid as an the growth of hSCDas cell cells was was cells and in a cell was by of synthesis of hSCDas and cells was the levels of as and C. J.Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). of cells with for the and hSCDas cellswere 1 cells in FBS, in the presence or of and a of in the presence or of cells) in cell was observed cell in for and of of was as described by A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). hSCDas cells and cells with of in for the cell with in with or of palmitic acid and/or acid to or for the cells was and the in a in and and for was and in the the cellular was and in and The of to the of by of or apoptosis by and described by K. S. Y. N. Y. Google Scholar). of and hSCDas cells in the and by cells and by several by in an was in cell using a the with used as positive for N. J.M. PubMed Scopus Google Scholar). of the content of cellular we a as described by J. J. Biol. Chem. Full Text PDF PubMed Google Scholar) and by C. J.Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). was to cellular protein of cellular was as described by J. Biol. Chem. Full Text PDF PubMed Google Scholar), using as or are and of the data or of A of SCD the MUFA in have reported that the of human fibroblast with the expression to a high in cell membrane and membrane N. J.M. PubMed Scopus Google Scholar). cells a neoplastic a replication and loss of C. J.Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). work, we SCD is for sustaining and phenotype of transformed cells by cells in SCD this of cells a of with a of human SCD cDNA in of SCD and because these exhibited the SCD expression In these SCD by the acid to was compared with cells, although to showed the SCD activity decrease to by and in SCD activity levels by and with cells. As the SCD activity was of SCD protein level in the hSCDas in of the the content of was compared with that the transfection of SCD cDNA cells to a of SCD protein and a in Because the exhibited the SCD this cell was most of the in the the decrease in SCD activity was a in cellular fatty acid acid of phospholipids was MUFA in as compared with the acid by acid acid by and acid levels increased by in the with to cells. palmitic not between the knockdown and cells. the was by in the with the of in the was by with not that the decrease in SCD activity by an in the of the fatty acid of the lipid and was the and MUFA to in phospholipids of cell of fatty acids in phospholipids by by by by by fatty by by by by by by by by by by by by by by by fatty in a SFA and has been shown that SCD activity is lipid in M. J.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google M. J.M. J. Lipid Res. 2001; Full Text Full Text PDF PubMed Google Scholar). data suggest that SCD in and neoplastic is with membrane lipid J.B. Ericsson J. Kallin A. Rorsman C. Ronnstrand L. Heldin C.H. J. Biol.Chem. 2004; 279: 35392-35402Abstract Full Text Full Text PDF PubMed Scopus (100) Google N. J.M. PubMed Scopus Google Scholar). between SCD and lipid synthesis in human cells, we the of acid was in cells. this cell and the with acid for and levels of As of the acid was the with the and In the and between and cell the we observed a of the acid in compared with cells of and in and cells, with also not these to that the level of acid is to the of The in the of and cells a of the acid and we the cells with acid for and the levels As shown of acid was phospholipids cells compared with empty and in hSCDas cells, a for saturated and fatty acids in cells, of acid for the of SCD to a in and the acid and was in hSCDas cells, we the synthesis of phospholipids and the major using as the the for the levels of The synthesis of was by and cells compared with A In of and was by and cells to by the of phospholipids using as a of the The of in not studies using as a that the synthesis of the membrane in was in cells not of and in have suggested that excess content for and M. Zhou M. S. A. PubMed Scopus Google P. A. M. M. D. L. S. A. PubMed Scopus Google Scholar). the has been that protects cells these M. A. D.L. 2001; PubMed Scopus Google Scholar). observed that hSCDas cells a that is acid but also have a with we their in to the observed lipid synthesis and fatty acid the cellular in and shown in content increased by in the cells with Interestingly, the composition of the was increase in the content of palmitic and acids The of MUFA in that, the the of using fatty acids, by a levels of FFA, the saturated within the cells havebeen to cell by and M. Zhou M. S. A. PubMed Scopus Google L.L. Ory D.S. Schaffer J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). content and of not in we the and composition in the cell to their cells showed a content the cell unesterified palmitic and acid levels increased that the the was to the increase in the SFA in cells was in cells acid for increased in compared with of the to for SFA, because no was observed the and cells with acid for of SCD the of the in that SCD expression levels in as well as the of synthesis of and cholesterol, we the as to by these in lipid the of synthesis in cells by As shown in hSCDas cell a synthesis of compared with the cells. cells, the SCD showed the in the cell cell levels of SCD synthesis by and cells. Interestingly, the of to the growth for to did not of hSCDas an of acid is for sustaining a high growth for cells cells The cells the most growth this growth was to the neoplastic growth of C. J.Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). In cells a slower with the cells Because SCD the proliferation neoplastic cell we transformed phenotype in hSCDas growth is a of neoplastic we to the of cells to a in of for to to the of in cells to cells to anchorage-independent the cells. Interestingly, did not of cells to that endogenously synthesized MUFA are by to their for anchorage-independent growth. SCD in a in suggested to have been for this excess M. Zhou M. S. A. PubMed Scopus Google Scholar), S. W. E. E. M. Y. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google of L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer S. A. 2003; PubMed Scopus Google Scholar). Most of the studies the effects of SFA cell to of these fatty acids. of SCD to the of of SFA either or is still this we the that the expression apoptosis by SFA of of was a for cell in cells and controlcells. As in the of apoptosis in in cells. The of apoptosis cells was by the presence of by with In activity was cell using cells as positive in cells showed a increase in activity cells, the positive SCD and cell The role of in the of apoptosis has been but the of levels and lipid has been observed that of SFA, in to cell M. Zhou M. S. A. PubMed Scopus Google in cell apoptosis to in aceramide-independent L.L. Ory D.S. Schaffer J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). we that the excess of saturated and by in SCD expression was in and cells growth observed that the levels of this lipid not between of as the of these a role for SCD in the of cell by are not through a studies have that high levels of SFA the of acid or of the cell L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer S. A. 2003; PubMed Scopus Google Scholar). In an to we and cells of palmitic acid for and the by the of the influence of fatty acids, these studies in a high the we used a fatty As shown cells exhibited a of cells. acid increased a manner in cell In with and palmitic acid increased the by and compared with controlcells. Interestingly, SCD the cells more to thecytotoxic of palmitic and the of cells increased and with to cells. the of MUFA and cells with palmitic acid and and of apoptosis was Interestingly, with acid apoptosis in hSCDas and cells to levels observed of no for cell of and with to their cell did not reverse the apoptosis cells. In more by a fatty of increased apoptosis the cells fatty acid high and fatty a almost to that in human J. Lipid Res. Full Text PDF PubMed Google Scholar), did not levels in either or cell not In the transfection of cells human SCD cDNA to a decrease in the expression the activity of SCD. was by a in the of the major membrane and in and The of SCD hSCDas was by a that SCD is the regulator of MUFA content cells. the of SCD in of SFA and MUFA is by the the in MUFA levels in cells presence of of MUFA in the growth In to the in fatty acid distribution in by SCD the overall phospholipids was in the cell that SCD a role not in the regulation acid of membrane but also in the synthesis of phospholipids in the Because a in fatty acid synthesis cells, the synthesis decrease in synthesized SCD to a role in the of the synthesis because SCD knockdown to a in thesynthesis of cholesterol, the major lipid in cell this it has been reported that the of cell growth factors in human cells a increase of SCD, with the of and J.B. Ericsson J. Kallin A. Rorsman C. Ronnstrand L. Heldin C.H. J. Biol.Chem. 2004; 279: 35392-35402Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). cellular and this lipid can a of fatty acids. excess content of a of in this the composition and membrane excess fatty acids an lipid we that showed a increase in the acid and with the and and with with no in MUFA this to in a of SCD to the membrane cells excess SFA the and these fatty acid the of also by the that in the content of the a of for the phospholipids and in a manner and to was and of a of SFA and MUFA lipid Our knockdown of SCD dramatic effects cell for hSCDas cells was to that was slower that of cells to C. J.Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). is of growth was to the in the of cells. a between and Because cells neoplastic the SCD knockdown their proliferation an of of the neoplastic cell is by that SCD in cells also of data that the high cellular SCD activity is for the cell proliferation and cells. this we a in SCD expression of cell proliferation and cells. of the in the growth cells are to by the of and/or cholesterol synthesis to a in the the of cell this for the observed synthesis for cell cycle S. J. Biol.Chem. Full Text PDF PubMed Google Scholar), of cell growth and M. M. H. J. Biol.Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). to a loss in cell growth and in human C. J.Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google K. A. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) and H. H. J. Google Scholar). In of phospholipids with SFA cells C.B. K. W. M. D. B. J. PubMed Scopus Google an of SCD in neoplastic cells by of B. J. C.B. K. W. J. PubMed Scopus Google Scholar). Finally, the fatty acid synthesis observed in cells also the decrease in cell In cells the fatty acid synthesis essential for sustaining a of fatty acid by cell proliferation and A. M. J. Biochem. 2004; PubMed Scopus Google Scholar). is also to that, by regulating SCD activity the of cells the of cellular by of lipid in influence that neoplastic cell and In this regard, SCD activity is known to regulate of that are in the membrane and (7Sun Y. Hao M. Luo Y. Liang C.P. Silver D.L. Cheng C. Maxfield F.R. Tall A.R. J. Biol.Chem. 2003; 278: 5813-5820Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar,8Hao M. Mukherjee S. Sun Y. Maxfield F.R. J. Biol. Chem. 2004; 279: 14171-14178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar). acid are known to important effects to cell proliferation and S. Y. M. Res. Google Scholar) and protein Res. 2003; PubMed Scopus Google Scholar). Our the first that SCD is cell and to studies a role for SCD in mammalian cells against Interestingly, cells apoptosis that SCD activity is cell The of the role of SCD is SCD activity is to the of SFA cells more sensitive to studies that that Chinese hamster are to L.L. Han X. Lewis S.E. Cases S. Farese Jr., R.V. Ory D.S. Schaffer S. A. 2003; PubMed Scopus Google Scholar). The Chinese hamster ovary cells, apoptosis was a high that cell and in and composition and observed in the are to to the of cell of in cells the apoptosis program high levels of SFA for the synthesis P. A. M. M. D. L. S. A. PubMed Scopus Google Scholar). of and in this the levels in cells of a of cell SCD the and N. J.M. PubMed Scopus Google Scholar), we have shown transformation a of by a of that the synthesis and SCD activity with a of with MUFA MUFA is an essential for synthesis of membrane because transformed cells of the of the membrane and cholesterol and N. J.M. PubMed Scopus Google Scholar). are for neoplastic cells to and metabolic to high of proliferation and to In we that SCD the and phenotype of SCD by SCD expression in to a decrease in the in a more cellular As a the of endogenously synthesized of acid phospholipids of is but this for the more saturated of membrane and The in SCDexpression also the synthesis of and in the content and membrane to in cell proliferation as observed in the hSCDas and fatty acid and are because of the these lipid to the saturated of these increased effects in cells, are to Prouty and for of human SCD are to for with and to for also and of the with