Fatty Acid Regulation of Gene Transcription

Abstract

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. 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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 (PEPCK) (a gluconeogenic enzyme) and actin genes was not affected by the treatment. Primary hepatocytes were then used to ascertain the direct nature of PUFA action (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). Moreover, transfection of hepatocytes with a chimeric gene containing −4315 to +19 base pairs relative to the transcriptional start site of the S14 gene linked to the chloramphenicol acetyltransferase structural gene demonstrated that the 5′-flanking region of the S14 gene was involved (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). The PUFA response element(s) was located between −220 and −80 base pairs of the S14 promoter (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). The question whether the actual modulators are PUFAsper se remains open. The observation that prostanoid inhibitors fail to prevent PUFA action suggests at least that prostanoids are not involved (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). Because the effect is restricted to PUFAs and because PUFAs are very sensitive to peroxidation, it is possible that cytotoxic peroxidative products could be the active molecules, a still debated issue (15Mikkelsen L. Hansen H.S. Grunnet N. Dich J. Biochim. Biophys. Acta. 1993; 1166: 99-104Crossref PubMed Scopus (25) Google Scholar, 16Foretz M. Foufelle F. Ferre P. Biochem. J. 1999; 341: 371-376Crossref PubMed Scopus (30) Google Scholar). This would be consistent with the fact that the effect of PUFA on transcription of genes coding for lipogenic enzymes is restricted to hepatocytes in which peroxidation occurs. Tissue-specific regulation by PUFA seems to occur in rat retroperitoneal, but not subcutaneous, WAT (17Raclot T. Groscolas R. Langin D. Ferre P. J. Lipid Res. 1997; 38: 1963-1972Abstract Full Text PDF PubMed Google Scholar). In 3T3-L1 adipocytes, arachidonic acid (C20:4n-6) suppressed lipogenic gene expression by a mechanism requiring cyclooxygenase and prostaglandin production (18Jump D.B. Thelen A. Mater M. Lipids. 1999; 34 (suppl.): S209-S212Crossref PubMed Google Scholar). Liver-specific transcription of at least two other genes, SCD1and apoA-1, is also a target of negative regulation by PUFA (19Ntambi J.M. J. Biol. Chem. 1992; 267: 10925-10930Abstract Full Text PDF PubMed Google Scholar, 20Landschulz K.T. Jump D.B. MacDougald O.A. Lane M.D. Biochem. Biophys. Res. Commun. 1994; 200: 763-768Crossref PubMed Scopus (117) Google Scholar, 21Berthou L. Saladin R. Yaqoob P. Branellec D. Calder P. Fruchart J.-C. Denefle P. Auwerx J. Staels B. Eur. J. Biochem. 1995; 232: 179-187Crossref PubMed Scopus (114) Google Scholar). In the SCD1 gene (and probably also the SCD2gene), the PUFA response region has been located in the promoter. However, the mechanism of repression is not yet resolved (reviewed in Ref. 4Sessler A.M. Ntambi J.M. J. Nutr. 1998; 128: 923-926Crossref PubMed Scopus (204) Google Scholar). Since the initial observation by Amri et al. (22Amri E.Z. Ailhaud G. Grimaldi P. J. Lipid Res. 1991; 32: 1457-1463Abstract Full Text PDF PubMed Google Scholar, 23Amri E.Z. Bertrand B. Ailhaud G. Grimaldi P. J. Lipid Res. 1991; 32: 1449-1456Abstract Full Text PDF PubMed Google Scholar) that FAs are inducers of the adipocyte lipid-binding protein (aP2) gene transcription in pre-adipose cells, evidence has accumulated demonstrating that FAs are potent regulators of the adipose differentiation process (adipogenesis). From a physiological viewpoint, it makes sense that FAs induce the expansion of WAT mass after an excess of food is ingested. Here, in contrast to the situation described above, saturated and unsaturated long chain FAs (C16 and longer) are equipotent. Therefore, it seems likely that the mechanism differs from that involved in the negative regulation of the liver lipogenic enzymes. The non-metabolizable FA α-bromopalmitate is also a that the metabolism of FAs is not Proc. Natl. Acad. Sci. U. S. A. 1992; PubMed Scopus Google Scholar). The of expression is and is by that protein synthesis is for the to occur (22Amri E.Z. Ailhaud G. Grimaldi P. J. Lipid Res. 1991; 32: 1457-1463Abstract Full Text PDF PubMed Google Scholar, 23Amri E.Z. Bertrand B. Ailhaud G. Grimaldi P. J. Lipid Res. 1991; 32: 1449-1456Abstract Full Text PDF PubMed Google Scholar). 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Biochimie (Paris ). 1997; 79: 129-133Crossref PubMed Scopus (46) Google Scholar), and in the line F. 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) induce 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. 1992; 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 situation more complex with the of other of the have been cloned and with and the to with retinoid X of which have also been (reviewed in Ref. B. Rev. 1999; PubMed Scopus Google Scholar). A cloned by and co-workers 1998; PubMed Scopus Google Scholar) is in expression of in cells adipocyte differentiation when like or polyunsaturated FAs, were provided P. 1994; 79: Full Text PDF PubMed Scopus Google Scholar). This observation that was the transcription factor of the adipocyte However, is not in pre-adipose cells, and an of is an of the that could play a role has been and is still a of C. D. D. C. Grimaldi J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The evidence 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, G. O. F. 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 observation that specific and are (reviewed in Ref. B. Rev. 1999; PubMed Scopus Google Scholar). The an arachidonic acid (C20:4n-6) of the is a very potent and specific The of is the most potent in a The is a a of and Therefore, these molecules could be for FA transcriptional This would however, that they are produced by the cells in which FAs are a debated issue. the described 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. B. 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. B. 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. B. Biol. 1999; PubMed Scopus Google Scholar). This is the for with apoA-1, SCD1, and This can be in and However, evidence suggests that of gene transcription by FAs and is genes that a not to FAs, as is the for instance, in hepatocytes L. Saladin R. Yaqoob P. Branellec D. Calder P. Fruchart J.-C. Denefle P. Auwerx J. Staels B. Eur. J. Biochem. 1995; 232: 179-187Crossref PubMed Scopus (114) Google Scholar) or in differentiated M. and C. Moreover, PUFAs transcription of the Δ-5 and Δ-6 desaturases (11Cho H.P. Nakamura M.T. Clarke S.D. J. Biol. 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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 PUFA is of and that the not bind the promoter Mater 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 evidence that transcription different from the could FA As mentioned above, other proteins the hepatic receptor was shown to bind R. J. I. J. 1998; PubMed Scopus Google Scholar). In transfection in cells, oleate and PUFAs potential of the apolipoprotein gene promoter chloramphenicol acetyltransferase expression. saturated FAs, and short chain palmitate was and (C18:0) was this observation has physiological remains an but not in it was shown that chain FAs can or action without with the binding of the to their elements J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). that FA could to gene transcription would be to the de novo synthesis of a as shown in of are of this is to the PUFA inhibition of lipogenic Because of between the negative control by FA and of their et al. T. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) the of PUFA 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 situation of was shown for the gene regulation in It was reported that PUFAs decrease gene expression and nuclear of in liver and in hepatocytes 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). Because is a positive of the FAS and S14 lipogenic genes, the reduction in of for the FA This observation is by of experiments with mice either N. H. M. H. F. J. T. R. S. N. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) or out for this gene H. N. M. J. F. T. S. N. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, the action 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. B. M. 1999; PubMed Scopus Google Scholar). In this FA the gene transcription rate 4 in Moreover, this was by of protein kinase and J. I. B. M. 1999; PubMed Scopus Google Scholar), corresponding to 1 in In the the response of the liver X to FAs has been S. O. Auwerx J. 2000; 14: PubMed Scopus Google Scholar). of rat cells or hepatocytes with unsaturated FAs an in protein, and gene transcription. Because is a nuclear receptor to be an important of and acid the observation that it is suggests that it a role in the between FA and regulation of metabolism. In the of and FAs modulate the amount of transcription as regulators of the expression of genes, which for proteins a metabolic It seems that depending upon the specific cell and target gene, FAs can very 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 Because it is that plasma FA concentration and have on to and it is of to the mechanisms by which these molecules gene transcription.