Fatty Acid Regulation of Gene Transcription

fatty acid long chain fatty acid polyunsaturated fatty acid non-esterified fatty acid white adipose tissue fatty acid transporter fatty acid-binding protein liver FABP acyl-CoA synthetase stearoyl CoA desaturase 1 liver-type pyruvate kinase apolipoprotein A-1 fatty acid synthase cytosolic phosphoenolpyruvate carboxykinase carnitine palmitoyltransferase acyl-CoA oxidase transcription factor peroxisome proliferator(s) peroxisome proliferator-activated receptor peroxisome proliferator-response element direct repeat 1 retinoid X receptor prostaglandin hepatic nuclear factor 4 sterol regulatory element(s) SRE-binding protein liver X receptor Fatty acids (FAs)1 are energy-rich molecules, which play important metabolic roles. They are also an integral part of cells as membrane components, which can influence fluidity and receptor or channel function. Over the past 10 years, it has become evident that FAs can also act as signaling molecules involved in regulating gene expression. For the most part, these target genes encode proteins with roles in FA transport or metabolism. The corresponding change in the amount of specific proteins is an adaptative process that the cells develop in response to variations in FA concentration in the vicinity of the target tissue. Although interesting progress has been made recently, the mechanism(s) by which FAs modulate gene transcription still remains largely unresolved. The purpose of the present review is to address this important issue. A comprehensive description of FA regulation of gene expression requires the understanding that 1) FA molecules have a common basic structure with specific diversity determined by chain length and degree of unsaturation and 2) FAs are rapidly metabolized. Long chain FAs (C16 and above) (LCFAs) can be either saturated or mono- or polyunsaturated (PUFA) depending upon the presence of one or more double bonds in the polycarbon chain. The most abundant monounsaturated FA is oleate, in which the chain has 18 carbons and the double bond is between C9 and C10 from the methyl end (C18:1n-9). The two major classes of PUFAs are n-3 (or ω3) and n-6 (or ω6), named for the carbon involved in the first double bond. The precursors of these two classes of FAs cannot be synthesized in humans and must be provided by the diet. Interestingly, n-3 and n-6 PUFAs may have biologically opposite properties, probably because they give rise to different eicosanoid products. For instance, when model animals with a propensity to develop tumors are fed diets containing a large proportion of n-6 PUFAs, tumor formation is favored, whereas diets with a similar proportion ofn-3 PUFAs are somewhat protective (see Ref. 1Cave Jr., W.T. FASEB J. 1991; 5: 2160-2166Crossref PubMed Scopus (168) Google Scholar for a review). Long chain FAs are insoluble in water and are carried in plasma either esterified in triacylglycerols arranged in complex structures, the lipoproteins, or in a non-esterified form (NEFAs) loosely bound to albumin (Fig. 1). Blood lipoproteins are synthesized from dietary lipids after absorption and re-esterification in the intestine (chylomicrons) or the liver (very low density lipoproteins). Plasma lipoproteins are hydrolyzed by hepatic lipase or by lipoprotein lipase to produce NEFAs that are locally taken up by the liver or by muscles and adipose tissue. In contrast, circulating NEFAs are produced almost exclusively by white adipose tissue (WAT) as a consequence of lipolysis from the stored triacylglycerols during periods of starvation. In lipogenic tissues like liver and WAT, FAs can also be synthetized de novo from glucose and esterified. Although butyrate, a short chain (four carbon, C4) FA, has been shown in some cases to exert regulation of specific genes besides its well known effect on chromatin, most of the reported actions of FAs on gene expression have been associated with LCFAs. Clearly in the cell, the signaling molecule is the free FA (not bound to albumin), which is transported in and out cells with the help of a membrane protein, the FA transporter (FAT). Six potential FAT candidates, the FA translocase (FAT-CD36), the FA transport protein, the mitochondrial aspartate aminotransferase, caveolin, the adipose differentiation-related protein, and the FA-binding protein (FABP, a cytosolic protein that can bind to membranes) have been cloned and characterized. In the cytoplasm, FAs are taken up by a cell-specific FABP and have alternate destinies (Fig. 1). They can be elongated, desaturated, β-oxidized in mitochondria or peroxisomes for energy production, submitted to a peroxidative process or to ω-oxidation in microsomes, exchanged with membrane phospholipids, and participate in or interfere with eicosanoid synthesis. It is, therefore, important to remember that whatever FA effect is investigated, not only FAs per se but also products of FA metabolism or FA-sensitive signal transduction cascade can act as a relay. FA regulation of gene transcription occurs in unicellular and complex organisms. In Escherichia coli, LCFAs are transported and activated as fatty acyl-CoAs catalyzed by FadD, the bacterial acyl-CoA synthetase (ACS). In this organism, CoA derivatives, not FAs, bind with high affinity to a transcription factor, the FaDR, preventing its binding to a response element, thereby allowing the gene involved in FA synthesis (fabA) to be repressed and genes encoding enzymes of FA transport and metabolism (fadL, fadD, fadE, fabBA, fadH) to be induced (reviewed in Ref. 2Black P.N. Faergeman N.J. DiRusso C.C. J. Nutr. 2000; 130 (suppl.): 305S-309SCrossref Google Scholar). In yeast, it appears that acyl-CoAs are also active in modulating gene transcription (reviewed in Ref. 2Black P.N. Faergeman N.J. DiRusso C.C. J. Nutr. 2000; 130 (suppl.): 305S-309SCrossref Google Scholar). Studies usingSaccharomyces cerevisiae focused on regulation of the OLE1 gene, which encodes the Δ-9 desaturase, a membrane protein that converts saturated palmitoyl (C16:0) and stearoyl (C18:0) CoA to their monounsaturated counterparts. As expected from the biological role of the desaturase, the rate of OLE1 gene transcription is increased in response to exogenous saturated FAs, whereas exposure to unsaturated FAs sharply reduces transcription (3Choi J.Y. Stukey J. Hwang S.Y. Martin C.E. J. Biol. Chem. 1996; 271: 3581-3589Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). The corresponding positive and negative response elements were located in the OLE1 upstream promoter region (3Choi J.Y. Stukey J. Hwang S.Y. Martin C.E. J. Biol. Chem. 1996; 271: 3581-3589Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar); however, the mechanisms of activation and of repression remain to be elucidated. In mammals, the expression of many genes has been shown to be modulated by FAs in a positive or a negative manner. However, in only a few cases has the transcription rate been clearly demonstrated as the main site of control. Post-transcriptional regulation can also occur, as exemplified by the PUFA-induced decrease in stability of stearoyl-CoA desaturase (SCD1) and glucose transporter 4 (GLUT4) mRNAs in the adipocytes of the 3T3-L1 cell line (reviewed in Ref. 4Sessler A.M. Ntambi J.M. J. Nutr. 1998; 128: 923-926Crossref PubMed Scopus (204) Google Scholar). This review focuses exclusively on the transcriptional aspects of FA control. Studies reporting mRNA variations in response to FAs without the demonstration, by run-on or transfection experiments in differentiated cells, that the rate of transcription is affected are mentioned only when pertinent. The control of hepatic lipogenic enzymes is currently the best example of negative regulation. Thirty years ago, Allmann and Gibson (5Allmann D.W. Gibson D.W. J. Lipid Res. 1969; 6: 51-62Abstract Full Text PDF Google Scholar) first observed that feeding mice with linoleate (C18:2n-6) greatly depressed hepatic lipogenesis and activities of fatty acid synthase (FAS), malic enzyme, and glucose-6-phosphate dehydrogenase, as would be expected from the physiology. Surprisingly, however, this effect appeared to be restricted to PUFAs, because neither palmitate (C16:0) nor oleate (C18:1n-9) was effective. Following this original observation, several studies showed that a PUFA-rich diet reduced the hepatic mRNA levels for FAS, acetyl-CoA carboxylase, L-PK, ATP citrate-lyase, malic enzyme, SCD1, apolipoprotein A-1 (apoA-1), the S14 protein (reviewed in Refs. 4Sessler A.M. Ntambi J.M. J. Nutr. 1998; 128: 923-926Crossref PubMed Scopus (204) Google Scholar and 6Clarke S.D. Jump D.B. Annu. Rev. Nutr. 1994; 14: 83-98Crossref PubMed Scopus (267) Google Scholar, 7Jump D.B. Clarke S.D. Annu. Rev. Nutr. 1999; 19: 63-90Crossref PubMed Scopus (546) Google Scholar, 8Pegorier J.P. Curr. Opin. Clin. Nutr. Metab. Care. 1998; 1: 329-334Crossref PubMed Scopus (36) Google Scholar, 9Niot I. Poirier H. Besnard P. Biochimie (Paris ). 1997; 79: 129-133Crossref PubMed Scopus (46) Google Scholar, 10Forest C. Franckhauser S. Glorian M. Antras-Ferry J. Robin D. Robin P. Prostaglandins Leukotrienes Essent. Fatty Acids. 1997; 57: 47-56Abstract Full Text PDF PubMed Scopus (29) Google Scholar), and more recently, Δ-5 and Δ-6 desaturases (11Cho H.P. Nakamura M.T. Clarke S.D. J. Biol. Chem. 1999; 274: 471-477Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 12Cho H.P. Nakamura M. Clarke S.D. J. Biol. Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar). The work of Clarke, Jump, and their co-workers (13Blake W.L. Clarke S.D. J. Nutr. 1990; 120: 1727-1729Crossref PubMed Scopus (119) Google Scholar, 14Jump D.B. Clarke S.D. MacDougald O. Thelen A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8454-8458Crossref PubMed Scopus (144) Google Scholar) provided insight into the mechanism by which FAS and S14 mRNAs are decreased by PUFAs. Blake and Clarke (13Blake W.L. Clarke S.D. J. Nutr. 1990; 120: 1727-1729Crossref PubMed Scopus (119) Google Scholar) showed that the reduction in hepatic FAS and S14 mRNAs following the administration to rats of a PUFA-rich diet was caused primarily by the inhibition of gene transcription. In that case, n-3 and n-6 PUFAs were both effective. This effect was specific because transcription of the cytosolic phosphoenolpyruvate carboxykinase and genes was not affected by the were to the direct of D.B. Clarke S.D. MacDougald O. Thelen A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8454-8458Crossref PubMed Scopus (144) Google Scholar). transfection of with a gene containing to to the transcriptional site of the S14 gene to the gene demonstrated that the region of the S14 gene was involved D.B. Clarke S.D. MacDougald O. Thelen A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8454-8458Crossref PubMed Scopus (144) Google Scholar). The response element(s) was located between and of the S14 promoter D.B. Clarke S.D. MacDougald O. Thelen A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8454-8458Crossref PubMed Scopus (144) Google Scholar). The the are se remains The that to that are not involved D.B. Clarke S.D. MacDougald O. Thelen A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 8454-8458Crossref PubMed Scopus (144) Google Scholar). the effect is restricted to PUFAs and because PUFAs are to it is that peroxidative products be the active molecules, a still J. 1993; PubMed Scopus Google Scholar, M. P. J. 1999; PubMed Scopus Google Scholar). This would be with the that the effect of on transcription of genes for lipogenic enzymes is restricted to in which regulation by to in but not D. P. J. Lipid Res. 1997; Full Text PDF PubMed Google Scholar). In 3T3-L1 acid lipogenic gene expression by a mechanism and prostaglandin D.B. Thelen A. M. 1999; (suppl.): PubMed Google Scholar). transcription of two is also a target of negative regulation by J.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Jump D.B. MacDougald Res. 1994; PubMed Scopus Google Scholar, P. D. P. P. J. J. PubMed Scopus Google Scholar). In the gene probably also the the response region has been located in the However, the mechanism of repression is not (reviewed in Ref. 4Sessler A.M. Ntambi J.M. J. Nutr. 1998; 128: 923-926Crossref PubMed Scopus (204) Google Scholar). the by P. J. Lipid Res. 1991; Full Text PDF PubMed Google Scholar, P. J. Lipid Res. 1991; Full Text PDF PubMed Google Scholar) that FAs are of the protein gene transcription in cells, has that FAs are of the adipose process a it that FAs the of after an of is in to the saturated and unsaturated long chain FAs (C16 and are it that the mechanism from that involved in the negative regulation of the liver lipogenic The FA is also a that the metabolism of FAs is not Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The of expression is and is by that protein synthesis is for the to P. J. Lipid Res. 1991; Full Text PDF PubMed Google Scholar, P. J. Lipid Res. 1991; Full Text PDF PubMed Google Scholar). This a direct of FA on gene but is with the that FAs act by the synthesis of either a transcription factor or of some protein with a that is for the effect (Fig. several mRNAs of the lipoprotein the protein are clearly induced by long of with The the that FAs the process but not give to the It is that a common response element(s) to a transcription factor is present in the promoter of these to the mechanism would be to in the genes when transcription is by FAs in differentiated adipocytes a when is not and the genes this P. J. Lipid Res. 1991; Full Text PDF PubMed Google Scholar, J. Robin P. Robin D. C. Res. 1994; PubMed Scopus Google J. Robin P. Robin D. C. J. PubMed Scopus Google Scholar). the in adipocytes of thereby re-esterification of FAs into during lipolysis and FA J. Biol. Chem. Full Text PDF PubMed Google Scholar). activation also of FAs in adipocytes after of a diet. a of FAs on is in with the glucose the FA J. Robin P. Robin D. C. Res. 1994; PubMed Scopus Google J. Robin P. Robin D. C. J. PubMed Scopus Google Scholar). it was shown that mono- and polyunsaturated FAs, but not saturated FAs, of This with the effect of on P. J. Lipid Res. 1991; Full Text PDF PubMed Google Scholar) or on carnitine palmitoyltransferase 1 and liver FABP in (see The effect of FA is not protein and on gene transcription. of C. Franckhauser S. Glorian M. Antras-Ferry J. Robin D. Robin P. Prostaglandins Leukotrienes Essent. Fatty Acids. 1997; 57: 47-56Abstract Full Text PDF PubMed Scopus (29) Google Scholar). of prostaglandin or synthesis nor can FA M. C. Chem. 1999; Scholar). Although it was that oleate gene expression in cells also J. Robin P. Robin D. C. Res. 1994; PubMed Scopus Google Scholar), it that of the gene by FAs occurs in adipocytes C. Franckhauser S. Glorian M. Antras-Ferry J. Robin D. Robin P. Prostaglandins Leukotrienes Essent. Fatty Acids. 1997; 57: 47-56Abstract Full Text PDF PubMed Scopus (29) Google Scholar). This in of the gene in two tissues may be to the in the of in from that in liver it is The expression of a of genes in the liver is positive FA control in a manner. the acyl-CoA oxidase the and the effect of FA on transcription has been determined for the P. D. P. P. J. J. PubMed Scopus Google Scholar), C. J. J. 1996; PubMed Scopus Google Scholar), and C. Poirier H. I. C. Besnard P. J. 1996; PubMed Scopus Google Scholar) for the and is restricted to saturated and unsaturated FAs and requires de novo protein synthesis J.P. Curr. Opin. Clin. Nutr. Metab. Care. 1998; 1: 329-334Crossref PubMed Scopus (36) Google Scholar, 9Niot I. Poirier H. Besnard P. Biochimie (Paris ). 1997; 79: 129-133Crossref PubMed Scopus (46) Google Scholar, C. J. J. 1996; PubMed Scopus Google Scholar, C. Poirier H. I. C. Besnard P. J. 1996; PubMed Scopus Google Scholar). in the of that of FA and of eicosanoid synthesis not J.P. Curr. Opin. Clin. Nutr. Metab. Care. 1998; 1: 329-334Crossref PubMed Scopus (36) Google Scholar, C. J. J. 1996; PubMed Scopus Google Scholar, de J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar). Interestingly, and genes are also induced by FAs in in the intestine I. Poirier H. Besnard P. Biochimie (Paris ). 1997; 79: 129-133Crossref PubMed Scopus (46) Google Scholar), and in the line S. M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In both saturated and unsaturated LCFAs have The main mechanisms of FA regulation of gene transcription are in FAs, or FA 1) a cascade of to a of a transcription factor for thereby its 2) bind to and a the mRNA stability or influence the transcription rate of a its de novo synthesis. The to a the element in the region of the target gene, either as a or as a or a Following the in by and I. S. 1990; PubMed Scopus Google Scholar) of a of the receptor the peroxisome proliferator-activated receptor the that it be the receptor This receptor is activated by the peroxisome and in a in which cells cells for their high transfection are with a expression and a gene the control of a transcription that a response element and activated by the an M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) and H. C. J. A. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: PubMed Scopus Google Scholar) first showed that FAs are The more complex with the of of the have been cloned and with and the to with retinoid X of which have also been (reviewed in Ref. Rev. 1999; PubMed Scopus Google Scholar). A cloned by and co-workers 1998; PubMed Scopus Google Scholar) is in expression of in cells when like or polyunsaturated FAs, were provided P. 1994; 79: Full Text PDF PubMed Scopus Google Scholar). This that was the transcription factor of the However, is not in cells, and an of is an of the that play a role has been and is still a of C. D. D. C. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The that FAs are for the in J. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, P. J.M. J.M. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar, O. M. 1997; PubMed Scopus Google Scholar). to some was shown FAs, PUFAs saturated FAs for to which palmitate (C16:0) bound with also was the that specific and are (reviewed in Ref. Rev. 1999; PubMed Scopus Google Scholar). The an acid of the is a and specific The of is the most in a The is a a of and these molecules be for FA transcriptional This would however, that they are produced by the cells in which FAs are a issue. the in Ref. 10Forest C. Franckhauser S. Glorian M. Antras-Ferry J. Robin D. Robin P. Prostaglandins Leukotrienes Essent. Fatty Acids. 1997; 57: 47-56Abstract Full Text PDF PubMed Scopus (29) Google Scholar, response elements have been in a of They of of a direct repeat of the by one to which the appears to be important for and of (reviewed in Ref. Rev. 1999; PubMed Scopus Google Scholar). an element is to bind in a A is also the for the and of nuclear and like hepatic nuclear factor 4 and upstream promoter transcription factor (reviewed in Ref. Rev. 1999; PubMed Scopus Google Scholar). A of genes shown to be also to and present a in their it has been that FAs gene transcription a process (reviewed in Ref. A. Biol. 1999; PubMed Scopus Google Scholar). This is the for with SCD1, and This can be in and However, that of gene transcription by FAs and is genes that a not to FAs, as is the for instance, in P. D. P. P. J. J. PubMed Scopus Google Scholar) or in differentiated M. and C. PUFAs transcription of the Δ-5 and Δ-6 desaturases (11Cho H.P. Nakamura M.T. Clarke S.D. J. Biol. Chem. 1999; 274: 471-477Abstract Full Text Full Text PDF PubMed Scopus (535) Google Scholar, 12Cho H.P. Nakamura M. Clarke S.D. J. Biol. Chem. 1999; 274: 37335-37339Abstract Full Text Full Text PDF PubMed Scopus (434) Google Scholar), whereas the genes are induced by but not in C. J. J. 1996; PubMed Scopus Google Scholar). of gene expression is by in whereas the FA effect is J.P. Curr. Opin. Clin. Nutr. Metab. Care. 1998; 1: 329-334Crossref PubMed Scopus (36) Google Scholar); the gene region two to bind a in a P. J. Biol. PubMed Google Scholar). It is to FAs in adipocytes but not in or cells (see however, large of In the S14 gene, negative element for the is clearly from that for PUFAs Thelen A. Jump D.B. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). were with the of In the administration of or the of PUFAs to repressed S14 and FAS gene expression of and mRNAs was Thelen J.M. Jump D.B. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). studies demonstrated that negative regulation of the gene by is of and that the not bind the promoter Thelen J.M. Jump D.B. J. Lipid Res. 2000; Full Text Full Text PDF PubMed Google Scholar). some of the FA but not can be to of that transcription different from the FA As mentioned proteins the hepatic receptor was shown to bind J. I. J. 1998; PubMed Scopus Google Scholar). In transfection in cells, oleate and PUFAs potential of the apolipoprotein gene promoter expression. saturated FAs, and short chain palmitate was and (C18:0) was this has remains an but not in it was shown that chain FAs can or without with the binding of the to their elements J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). that FA to gene transcription would be to the de novo synthesis of a as shown in of are of this is to the inhibition of lipogenic of between the negative control by FA and of their J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) the of on genes sterol regulatory elements in their In cells they that oleate and PUFAs reduced expression of genes by the of SRE-binding protein FAs were a of was shown for the gene regulation in It was reported that PUFAs decrease gene expression and nuclear of in liver and in but not in 3T3-L1 adipocytes J. Nakamura M.T. H.P. Clarke S.D. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, Thelen Jump D.B. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). is a positive of the FAS and S14 lipogenic the reduction in of for the FA This is by of experiments with mice either H. M. H. J. S. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) or out for this gene H. M. J. S. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, the of PUFAs on is as exemplified by in but the mechanism has not been the of the response genes in the line by palmitate and oleate but not by PUFAs J. I. M. 1999; PubMed Scopus Google Scholar). In this FA the gene transcription rate 4 in this was by of protein kinase and J. I. M. 1999; PubMed Scopus Google Scholar), corresponding to 1 in In the the response of the liver X to FAs has been S. O. J. 2000; 14: PubMed Scopus Google Scholar). of cells or with unsaturated FAs an in protein, and gene transcription. is a nuclear receptor to be an important of and acid the that it is that it a role in the between FA and regulation of metabolism. In the of and FAs modulate the amount of transcription as of the expression of which for proteins a metabolic It that depending upon the specific cell and target gene, FAs can different to transcription. Although the of mechanisms are still progress have been made recently, with the help of mice in which specific transcription or nuclear were either or by In studies and of specific cell from these mice would the of the protein as a that the mechanism has been to may be to the of structure that to the of in the rapidly of on and the transcriptional of specific nuclear it is that plasma FA concentration and have on to and it is of to the mechanisms by which these molecules gene transcription.