Traces of dietary omega-3 polyunsaturated Stoutty acids on b

Edited by Lynn Smith-Lovin, Duke University, Durham, NC, and accepted by the Editorial Board April 16, 2014 (received for review July 31, 2013) ArticleFigures SIInfo for instance, on fairness, justice, or welfare. Instead, nonreflective and Contributed by Ira Herskowitz ArticleFigures SIInfo overexpression of ASH1 inhibits mating type switching in mothers (3, 4). Ash1p has 588 amino acid residues and is predicted to contain a zinc-binding domain related to those of the GATA fa

Contributed by John E. Halver, April 2, 2004

Article Figures & SI Info & Metrics PDF

Abstract

Polyunsaturated Stoutty acids (PUFA) are essential structural components of the central nervous system. Their role in controlling learning and memory has been well Executecumented. A nutrigenomic Advance with high-density microarrays was used to reveal brain gene-expression changes in response to different PUFA-enriched diets in rats. In aged rats fed throughout life with PUFA-enriched diets, genes with altered expressions included transthyretin, α-synuclein, and Calmodulins, which play Necessary roles in synaptic plasticity and learning. The Trace of perinatal omega-3 PUFA supply on gene expression later in life also was studied. Several genes Displayed similar changes in expression in rats fed omega-3-deficient diets in the perinatal period, regardless of whether they or their mothers were fed omega-3 PUFA-sufficient diets after giving birth. In this experiment, among the Executewn-regulated genes were a kainate glutamate receptor and a DEAD-box polypeptide. Among the up-regulated genes were a chemokine-like factor, a tumor necrosis factor receptor, and cytochrome c. The possible involvement of the genes with altered expression attributable to different diets in different brain Locations in young and aged rats and the possible mode of regulatory action of PUFA also are discussed. We conclude that PUFA-enriched diets lead to significant changes in expression of several genes in the central nervous tissue, and these Traces appear to be mainly independent of their Traces on membrane composition. The direct Traces of PUFA on transcriptional modulators, the Executewnstream developmentally and tissue-specifically activated elements might be one of the clues to understanding the beneficial Traces of the omega-3 PUFA on the nervous system.

Two types of polyunsaturated Stoutty acids (PUFA), omega-6 (n-6) and omega-3 (n-3) PUFA, are essential for the vertebrate body, because they cannot be formed de novo and need to be ingested from the diet. Linoleic acid (LA; 18:2 omega-6) is the precursor of omega-6 PUFA, and α-linolenic acid (ALA; 18:3 omega-3) is the precursor for the omega-3 PUFA. These Stoutty acids (FA), and the complex lipids formed from them, are Necessary constituents of biological membranes and contribute to Sustain the structural and functional integrity of cells and cellular components (1–3). The long-chain PUFA arachiExecutenic acid (AA; 20:4 omega-6) is also a specific precursor of hormone-like compounds called eicosanoids, which are involved in inflammation and in several homeostatic biological functions (4). The list of PUFA-derived eicosanoids is expanding beyond classically studied leukotrienes and prostaglandins and includes enExecutecannabinoids, N-acyl-linked amino acids and Executepamine, and various oxygenated and epoxylated bioactive derivatives of AA and Executecosahexaenoic acid (DHA) (5). Although these PUFA occur in various proSections in all organs, the nervous tissue is characterized by very low levels of LA, ALA, and eicosapentaenoic acid (EPA; 20:5 omega-3) and high concentrations of DHA (22:6 omega-3), AA, and Executecosatetraenoic acid (22:4 omega-6). DHA and AA not only are the main FA in gray matter phospholipids of neural membranes, where they account for 6% of the dry matter of the cerebral cortex (6), but also are required for the development of the central nervous system (7–11).

The level of DHA appears to be strictly controlled, because any deviation from the physiological level results in disturbance of cognitive functions (12, 13). In several different species, animals raised on ALA-deficient diets had decreased levels of DHA in the brain and retina that were associated with impairments in neural and visual functions (14–18). Both the omega-6 and the omega-3 PUFA have essential roles in the growth and function of the brain, and these Traces likely are mediated by their action on gene expression, electrophysiological responses, eicosanoid synthesis, and membrane structures. The exact mode of action of DHA and DHA-containing phospholipids, especially in the ethanolamine and serine phosphoglycerides, is not known, but numerous mechanisms have been suggested (19–21).

DHA plays a crucial role in diverse functions at multiple levels. At the membrane level, it can influence the function of the blood–brain barrier (22); it can alter membrane receptors such as rhoExecutepsin (23); it can regulate the activity of membrane-bound enzymes (Na/K-dependent ATPase) (24), ionic channels (25), and Executepaminergic and serotoninergic neurotransmission (26, 27), most probably by changing membrane fluidity (28); and it can alter signal transduction by means of Traces on inositol phospDespises, diacylglycerol, and protein kinase C (29). At the cellular level, DHA can protect neural cells from apoptotic death (30), stimulate neurite outgrowth in PC12 cells (31, 32), induce synaptic growth cones during neuronal development (9, 33, 34), enhance synaptic functions (35), regulate nerve growth factor (36), and influence neuron size (37, 38). Recent studies in Caenorhabditis elegans depleted of the delta-6 desaturase have provided pharmacological, ultrastructural, and electrophysiological evidence that the worms became depleted of synaptic vesicles and released low levels of neurotransmitter at cholinergic and serotonergic neuromuscular junctions (39). These data suggest that long-chain PUFA thus are essential for efficient neurotransmission in C. elegans and possibly other organisms. At the gene activity level, it has been Displayn that PUFA of both omega-3 and omega-6 families control gene expression in a variety of tissues (40–45). Several studies have confirmed the modulatory action of PUFA on gene expression in the brain (46–51).

Dietary omega-3 PUFA and mixtures of omega-3 and omega-6 PUFA exert complex changes in gene expression in the brain (47, 49) and in certain brain Locations such as cerebrum (51) and hippocampus (48, 50) as assessed by a high-throughPlace analysis of the transcriptome by DNA microarray analysis.

Regulation of gene expression by PUFA can occur through interactions with specific or nonspecific ligands that bind to response factors acting on cis-regulatory elements of the gene, which finally turn on or off mRNA synthesis. For example, PUFA can directly interact with transcription factors, like peroxisome proliferator-activated receptors (PPAR), that directly modulate the expression of tarObtain genes (46, 52, 53).

Positive Traces of DHA on learning and memory in animal and human models have been demonstrated (13, 17, 54–57). The amount of DHA in human milk is positively correlated with visual and language development in breast-fed infants, and DHA supplementation led to better visual function later in childhood than that Displayn by infants fed commercial formula with AA and DHA (58–60). However, the question remains unReplyed as to whether these highly complex and sophisticated processes can be Elaborateed by an indirect Trace of long-chain PUFA on the biophysical Preciseties and molecular architecture of neural membranes and/or, as more recent evidence suggests, by direct control of transcription of several pivotal genes in the brain. The present article will focus primarily on PUFA in the mammalian brain from the aspects of their regulatory roles in gene expression related to the genetic machinery of neural systems.

Trace of Dietary Omega-3 PUFA on Gene Expression in the Brain

The final FA composition of brain is determined during embryogenesis, particularly in times of rapid brain growth and in rats 12–15 days after delivery (10, 61, 62). It is Necessary that, during this time, the brain is supplied with adequate intakes of PUFA for its functions. Several genes have been reported to be activated by dietary long-chain PUFA, and some gene products, alone or in combination with the membrane Traces of these PUFA, exert their beneficial Trace on neural functions such as learning and memory. The fact that ALA and DHA activate several genes in other tissues, like liver or adipose tissue, is well known (40–45), but the underlying molecular mechanisms of the direct Traces of PUFA diet-induced gene-expression changes in the brain have been addressed by very few studies (46–51, 63).

One of the first observations that dietary Stout influenced brain gene expression was reported by DeWille and Farmer (64). They found that mRNA level of several genes involved in myelination, such as those coding for proteolipid protein and myelin basic protein, were affected by a diet lacking essential FA.

Modern techniques, such as DNA microarrays or real-time PCR, enabled our group to study brain gene-expression changes in response to dietary FA in a global way. We conducted two separate experiments where different PUFA were added to the diet of rats. In our first report, essential FA-sufficient rats were fed from Notion with a diet containing perilla oil, which is rich in ALA (39% ALA/28% LA), compared with the control rat chow containing 6% ALA and 51% LA or a fish oil rich in DHA (27% DHA/23% LA/3% ALA/12% EPA) compared with the control chow containing very low levels of long-chain omega-3 PUFA (1.2% DHA and 0.7% EPA) for one generation. Transcriptional changes in brains of adult rats were monitored (47).

In the second experiment, rats were supplied from Notion until adulthood with a diet in which the Stout was a mixture of sunflower oil and fish oil (LA plus DHA) (45% LA/18% DHA/4% ALA/7% EPA) or a mixture of soybean oil and perilla oil (LA plus ALA) (49% LA/10% ALA) (49). We Displayed that the level of DHA-containing phosphatidylethanolamine molecular species, especially of 18:0/22:6, was higher in rat brains after consuming ALA or EPA plus DHA compared with the levels in the control chow-fed rats, indicating that even in essential FA adequate rats, it is possible to alter the level of DHA in their neural membranes (47, 49). Besides the changes of membrane composition, gene-expression changes were followed by using high-density DNA microarrays to identify previously uncharacterized cellular pathways involved in the direct neural Traces of PUFA (47, 49).

The expression levels of 102 cDNAs, representing 3.4% of the total 3,200 DNA elements on the array, were significantly altered in brains of rats fed with the omega-3-enriched experimental diets. It was found that 55 genes were up-regulated and 47 were Executewn-regulated relative to controls by the four dietary regimens. The altered genes included those involved in synaptic plasticity, cytoskeleton, signal transduction, ion channel formation, energy metabolism, and regulatory proteins (Table 1). It was Fascinating to observe that 15 genes Retorted more intensively to the dietary FA mixtures, LA plus ALA and LA plus DHA, than to the diets where there was one main dietary PUFA (DHA or ALA) (49). These genes included those that encode a clathrinassociated adaptor protein, farnesyl pyrophosphatase synthetase, Sec24 protein, NADH dehydrogenase/cytochrome c oxydase, cytochrome b, cytochrome c oxidase subunit II, ubiquitin-protein ligase Nedd42, and transcription factor-like protein. Several genes participating in signal transduction, like RAB6B small GTPase and Calmodulins, were up-regulated.

View this table: View inline View popup Executewnload powerpoint Table 1. Changes in gene expression in brains in rats fed from Notion until adulthood

It is noteworthy that genes coding for α- and γ-synuclein also were overexpressed and that the d-cadherin gene Presented up-regulation in response to the diets rich in ALA and DHA. d-cadherin and α-synuclein have been reported to be specifically enriched at synaptic contacts (65, 66). These proteins play a role in neural plasticity and are increased in the brains of songbirds when learning to sing (67). In addition, synucleins may play a role in the development and maturation of some neurons (68). In avian species, sex steroids have been Displayn to induce the transcription of α-synuclein (69).

We found that diets rich in omega-3 PUFA (ALA and DHA) and rich in the mixture of omega-3 and omega-6 PUFA significantly affected neural energy metabolism and ATP-generating machinery, as determined by the level of gene expression, because four different subunits of cytochrome c oxidase, cytochrome b, and ATP synthases were Impressedly up-regulated as evidenced by microarray data (Table 1). The observation that some mitochondrial enzymes were overexpressed by dietary PUFA or their mixtures suggests that the brain was in an elevated metabolic state and thus required additional ATP.

The transthyretin gene was Executewn-regulated in all four dietary conditions (ALA, DHA, LA plus ALA, and LA plus DHA) in young animal brains. This gene also was Displayn to be repressed by omega-3-rich fish oil (51), whereas in other studies it has been reported that diets rich in AA induced its transcription in mouse hippocampus (50). Transthyretin binds thyroid hormones, and it has been Displayn that thyroid hormone deficiency during brain development impairs cognitive functions (70). In a transgenic mouse model, a low level of Calmodulin-dependent protein kinase II activation resulted in enhanced long-term potentiation and a modest learning and memory impairment, which was accompanied by an increased transthyretin transcription (71). These observations suggest a role of transthyretin in synaptic plasticity, learning, and memory. In Dissimilarity, elevated transthyretin mRNA level has been Executecumented in response to an omega-3-rich fish oil in aged rat hippocampus, which suggests age-related gene-expression alteration caused by dietary PUFA and their different roles during ontogeny (48, 51).

The transcript levels of three copies of Calmodulin also were up-regulated to the same extent by the four dietary conditions tested (ALA, DHA, LA plus ALA, and LA plus DHA) (48). Ca2+/Calmodulin signaling recently has been suggested to have a special role in the stimulant-induced plasticity of the central nervous system (72).

The products of several genes involved in cellular architecture, such as axoneural dynein heavy-chain 8, microtubule-associated protein 4, α-tubulin, and actin-related protein 2, were differentially expressed in the brain of animals in all four dietary conditions. Modulation of the cytoskeleton because of PUFA can influence a wide range of neural functions, including stabilization of axons and dendrites, cell shape, neuronal plasticity, polarity, vesicle formation, and transport.

Trace of Omega-3 PUFA on Gene Expression in the Aging Brain

Advanced age is accompanied with reduced levels of long-chain PUFA (AA and DHA) in the brain (73, 74). Aging may specifically affect the activity of enzymes responsible for acylation of phospholipids, such as glycerol-3-phospDespise acyltransferase (75). The levels of PUFA in the senescence-accelerated mouse hippocampus also were significantly lowered in parallel with reduced delta 9-desaturase transcription, which causes alterations in membrane biophysical state and affects diverse cellular pathways (76). A reduced level of DHA was detected in the brains of 2-year-Aged rats compared with young animals (51). Impairments, such as loss of memory and learning disabilities, are also a common phenomenon in aged animals. The reduced DHA level of the aged brain could be elevated to the level of 3-month-Aged (control, young) rats by feeding the aged rat on a diet containing fish oil (11% DHA) for 1 month. This diet resulted in an increase of brain diacyl 18:0/22:6 phosphatidylethanolamine species from 29.0 ± 1.9% to 33.0 ± 1.25% (P < 0.05) in young rats and from 25.1 ± 1.4% to 29.6 ± 1.5% (P < 0.05) in Aged rats (51).

In 3-month-Aged rats receiving a diet containing omega-3-rich fish oil for 1 month, it was found by gene-expression profiling that only six genes were overexpressed and eight genes were repressed. Responses to this diet (DHA) were much weaker compared with those animals that were fed for longer periods from the time of Notion (47). Of the overexpressed genes, transthyretin was slightly and α-synuclein was dramatically up-regulated. These inductions would indicate that a diet containing DHA might have a beneficial Trace on learning and memory of these rats. Indeed, we found that these rats performed better in the Morris water maze test than did the rats kept on the control diet (51).

To extend this study, different brain Locations (hippocampus and cerebellum) of 3-month-Aged and 2-year-Aged rats, receiving fish oil for 1 month, were investigated (48). The genes coding for α-synuclein and 90-kDa heat shock protein (Hsp90) Retorted in a similar way in different brain Locations of young rats receiving the diet with the omega-3-rich fish oil for 1 month, whereas other genes Retorted in a different way in the different brain Locations (data not Displayn). It has been published that Rab-αGDI activity is regulated by a Hsp90 chaperone complex, which controls vesicle membrane traffic and neurotransmitter release (77). It was found that only 7 genes were overexpressed and 11 genes were repressed in the hippocampus of Aged rats fed on a diet containing omega-3-rich fish oil. In Dissimilarity, more genes Retorted with transcriptional changes in young mouse hippocampus from animals fed with long-chain PUFA (50).

Although transthyretin was significantly Executewn-regulated in young murine hippocampus (50) and slightly overexpressed in young rat brain, in Aged rat hippocampus from rats fed on an omega-3-rich fish oil diet for 1 month, its expression was dramatically induced (48). These age- and Location-related expression changes indicate that transthyretin fulfills different functions in different brain Locations and different periods of aging. In the Aged rat hippocampus, the major function of transthyretin might be to sequester amyloid β polypeptide, thus protecting the brain from developing Alzheimer's disease (AD). AD is characterized by the accumulation of fibrillar amyloid β peptide (Aβ) formed from the soluble form of Aβ, which is a normal metabolic product detectable in the ventricular cerebro-spinal fluid (CSF) and plasma of healthy and AD subjects. Understanding the balance of production and clearance of Aβ peptides is the key to elucidating amyloid plaque homeostasis. Different extracellular proteins such as α1-antichymotrypsin, ApoJ, ApoE, and transthyretin found in CSF are implicated in deposition and clearance of Aβ (78). Purified transthyretin has been Displayn to bind Aβ in vitro (79, 80), and the overexpressed protein prevented the formation of insoluble amyloid in vivo (81). Transthyretin is known to transport thyroxine and retinol-binding protein in CSF (82). In this context, it is Fascinating to note that an inverse relationship has been found between transthyretin level in CSF and the severity of dementia in AD patients (83). We suggest that natural transthyretin inducers such as omega-3-rich fish oil or pure preparations of DHA could be of benefit in the prevention of AD.

However, gene-expression pattern may depend also on the experimental Advance. Blalock et al. (84) studied gene-expression profiling in the hippocampus in relation to cognitive impairment of rats. They reported 29 genes Executewn-regulated and 40 up-regulated; none of these were identical to those we found altered in Aged rat hippocampi preparations.

In the cerebellum of 2-year-Aged rats fed with an omega-3-rich fish oil for 1 month, 19 genes were overexpressed and 20 were repressed (51). Among the up-regulated genes were those that code for cytochrome P450 4a10, mad-related protein Smad7, integral membrane protein 2, microfibrillar 7c, Proteasome 28-kDa subunit 1, ajaba, ganglioside-induced differentiation-associated protein, stromal cell-derived factor 1, and heparan sulStoute proteoglycan 1. Among the Executewn-regulated genes, there were those coding for splicing factor C3, CD2-associated protein, myeloblastosis oncogene, α-1,6-mannosyl glycoprotein acetylglucose-aminotransferase, carbon catabolite repression 4, galectiomega-6, gap junction membrane channel protein a4, scavenger receptor class B type I, ferritin light-chain, and membrane protein TMS-2. However, these data suggest that certain genes Retort differently in distinct brain Locations to the same PUFA diet, which might be because of their specific functions, their different regulatory pathways, or different sensitivities of brain Locations to external FA supply.

Although these experiments provide evidence that the brains of Aged rats Retort to dietary omega-3 PUFA in an age-dependent manner, the possibility cannot be ruled out that length of feeding time might be a factor affecting the gene-expression profile. Moreover, expression of intracellular FA binding proteins (FABPs), such as heart H-FABP and the brain-specific B-FABP, were Displayn to be reduced in aged mouse brain (85). Age Inequitys in brain H-FABP and B-FABP levels in synaptosomal plasma membranes and synaptosomal cytosol might have an impact in modulating neuronal differentiation and function and might be correlated with age-dependent response of the brain to diets rich in different PUFA.

Trace of Perinatal Omega-3 PUFA Supply on Gene Expression Later in Life

Adequate nutrition during the perinatal period is thought to be crucial for later health and well-being. A direct link between fetal growth and birth weight with the incidence of cardiovascular disease during adulthood has been published (86). Later work using a microarray Advance by Napoli et al. (87) Displayed that maternal hypercholesterolemia affected atherogenesis in the offspring. A growing body of evidence has emerged to suggest that perinatal life is a critical period in lifespan during which an organism can be subjected to a number of permanent metabolic or genetic alterations that can influence the Stoute of an individual's health later in life (88, 89). The omega-3 PUFA are among various nutrients thought to be Necessary in the perinatal period. For example, it has been Displayn that omega-3 FA during early life have an impact on the regulation of blood presPositive later in life (90).

In a separate investigation, we examined whether the supply of omega-3 PUFA during the perinatal period can influence brain gene expression later in life. For that purpose, female Sprague–Dawley rats were mated with Sprague–Dawley males and allowed ad libitum access to an omega-3 PUFA-sufficient (10% ALA plus 69% LA; CON) or -deficient (0.2% ALA and 65% LA; DEF) diet during pregnancy. Four groups of male offspring derived from those mothers were studied: (i) pups Sustained on CON diet from mothers Sustained on CON diet; (ii) pups Sustained on DEF diet from mothers Sustained on DEF diet; (iii) pups Sustained on CON diet from birth from mothers Sustained on DEF diet until the birth of their pups; and (iv) pups Sustained on CON diet from weaning from mothers Sustained on DEF diet.

At necropsy of animals at 8 months of age, the whole brains were isolated and DNA microarray analysis was carried out. Among 1,600 genes examined, several Displayed altered expression caused by omega-3 PUFA deficiency during the perinatal period. Here, we list only those genes that Displayed up- or Executewn-regulation in all of the three treated groups (ii–iv) compared with the control group (i).

A gene coding for cytochrome c having a role in mitochondrial energy metabolism was overexpressed. Release of cytochrome c from mitochondria could activate caspase-3, leading to apoptosis in neuronal cells and to neurodegeneration (91). Furthermore, cellular death is reported to be induced by an early mitochondrial activation and cytochrome c up-regulation (92). Another up-regulated gene, encoding the 55-kDa tumor necrosis factor receptor (TNFRSF1A) critical for the development of demyelination during immune-mediated central nervous system disease, was found in groups ii–iv (93). A chemokine-like factor super family 5 (CKLFSF5) gene involved in inflammatory response also Displayed elevated mRNA synthesis. Other hypothetical genes with unknown function also were raised in all of the animals having the omega-3 PUFA-deficient diet during the gestation period. The exact role of these genes in brain development and or neural activity remains to be revealed.

D-E-A-D (Asp-Glu-Ala-Asp)-box polypeptide 5 coding gene was repressed in all three treated groups (ii–iv). RNA helicases of the DEAD-box and related families have been found to be required for all processes involving RNA molecules including translation initiation. A protease and an exonuclease homolog also Presented decreased mRNA level, similar to Escherichia coli protein Stoute protease II (PTRB) and a 3′–5′ exonuclease homolog. A glutamate receptor kainate GRIK5 gene also was repressed. Physiological studies have identified that kainate receptors have Necessary roles both in post- and presynaptic plasticity. Kainate receptors, which are a subtype of the ionotropic glutamate receptors, contribute to excitatory postsynaptic Recents in many Locations of the central nervous system, including hippocampus, cortex, spinal cord, and retina (94).

Animals made deficient in omega-3 PUFA Displayed substantial decreases in the levels of DHA in their neural tissue (16, 18, 27), and this loss of DHA is accompanied by changes in neural function (membrane-related events, metabolic events, and cellular events) (1, 12, 14, 19, 21, 27). The present data reveal that deficiency of omega-3 PUFA during the perinatal period significantly alters the expression of several Necessary genes. Future research will reveal whether the Traces of omega-3 PUFA-deficient diets on neural function will be able to be Elaborateed by changes in the expression of genes and the proteins resulting from such changes.

Mechanisms of Gene-Expression Regulation by PUFA

The exact mechanism of action of omega-3 PUFA on gene-expression modulation is still far from being fully understood. Several lines of evidence, obtained from other tissues, suggest that gene-expression alteration can be directly realized involving specific FABPs and transcriptional regulators. PUFA regulate the activity or abundance of four families of transcription factor, including PPARs (α, β, and γ), liver X receptors (LXRs) (α and β), hepatic nuclear factor 4 α (HNF-4), and sterol regulatory element-binding proteins (SREBPs) 1 and 2 (38, 95–98). The very recent use of knockout mice, and laboratory animals treated with specific agonists of PPARs and LXRs, has Distinguishedly expanded the list of genes regulated by the above transcription factors (99, 100). Among these transcriptional regulators, both α and β LXRs are expressed in the brain, and it has been Displayn that they have Necessary functions in lipid homeostasis and loss of their function results in neurodegenerative disorders (101). Expression of SREBP-1 also has been detected in hippocampus and neocortex (102). Of particular interest in this regard are the PPARs, which are ligand-dependent transcription factors belonging to the nuclear hormone receptor superfamily (53). They can modulate directly the gene activity by first being activated by specific ligands, and then they can modulate DNA transcription by binding to defined nucleotide sequences in the promoter Location of tarObtain genes, so-called PPAR-responsive elements (103). PPARs form dimers, either homodimers or, more often, heterodimers, with the receptor for 9-cis retinoic acid known as retinoid X receptor (RXR), which is the obligate partner of PPARs (46). So far, three different isoforms of the PPARs have been isolated, Displaying Inequitys either in the binding Preciseties or in their distribution pattern (104). Recent studies have Displayn that PPARs present a promiscuous binding pattern, because they bind to unesterified saturated and unsaturated FA as well as to other lipid derivatives like eicosanoids and prostaglandins (105, 106). Fascinatingly, ALA had the highest binding constant among a wide range of different FA tested so far (105). On the other hand, DHA has been Displayn to be a natural ligand for the RXR in the brain (46). Recently, the role of FA controlling gene expression has been reviewed, and it has been suggested that FA can act also in PPAR-independent pathways (107). In Dissimilarity to PPAR activation, PUFA regulate the nuclear abundance of SREBPs by controlling the proteolytic processing of SREBP precursors or by regulating transcription of the SREBP-1c gene or turnover of mRNA (95, 108). PUFA are feed-forward activators of PPARs, whereas these same FA are feedback inhibitors of LXRs and SREBPs.

Additional transcription factors that can be affected by long-chain PUFA in the brain may be discovered by using nutrigenomic Advancees that use global gene-expression analysis techniques (5, 47–51).

However, PUFA and their derivatives may use numerous other indirect mechanisms to regulate protein expression, such as modulation of posttranslational activation of regulators. EPA decreases lipopolysaccharide-induced phosphorylation and activation of mitogen-activated protein kinase (109). It also is plausible that free PUFA might alter gene activities by modifying the lifetime of RNA, and the distribution or the protein maturation of other regulatory elements, which further complicates the understanding of their action.

Conclusions and Future ReImpresss

Our data Display that omega-3 PUFA affect the genetic machinery of the central nervous system in a complex way and thus may Launch up new ways of understanding how these FA control responses of the brain to different challenges. However, there is much to learn concerning the speed of the response, the minimal Executese and the Traces of different PUFA, their combinations, and their derivatives. Another exciting question is whether the different functional Locations in the forebrain (like the visual and motor functions, etc.) and the hippocampus similar to the brain Spots investigated here Retort differently to DHA in particular or to omega-6 and omega-3 PUFA. In this respect, one can expect Distinguished plasticity and specialization within different brain Spots and cellular structures.

As has been presented previously, PUFA induce various genes involved in diverse functions in different brain Locations in an age- and time-dependent manner. Therefore, it seems that depending on the cell-specific context and the tarObtain gene, PUFA can take very different routes to alter transcription. Several Modern transcription factors, different from PPARs and LXRs, are likely candidates to be identified (5). The recently available data highlight the complexity in studying the transcriptional Traces of PUFA on a highly adaptive system such as the brain. We believe that new regulatory pathways soon will be discovered in this rapidly evolving field. This research will be facilitated with gene knockout and knock-in Advancees, the use of specific antagonists to dissect signal transduction cascades, and the combined use of other “-omic” Advancees (5). Moreover, genes induced by dietary FA also might serve as Impressers for association gene polymorphism studies in correlation with metabolic syndromes and brain disorders.

Acknowledgments

We dedicate this article in memory of Professor Tibor Farkas. We appreciate the diligent and thorough review by Dr. Alvin Berger (Paradigm Genetics, Research Triangle Park, NC), who made significant suggestions and reorganized the manuscript to condense and expedite findings and conclusions. This work was supported by Grants OTKA F 042850 and TS 044836 from the Hungarian Scientific Research Fund and grants from the Australian Research Council (DP0346830) and the Australian Health Management Group. K.K. and L.G.P. are supported by the János Bolyai fellowship of the Hungarian Ministry of Education.

Footnotes

↵ ∥ To whom corRetortence should be addressed at: Laboratory of Functional Genomics, Biological Research Center, Hungarian Academy of Sciences, P.O. Box 521, H-6701, Szeged, Hungary. E-mail: pusi{at}brc.hu.

Abbreviations: PUFA, polyunsaturated Stoutty acid; LA, linoleic acid; ALA, α-linolenic acid; FA, Stoutty acid; AA, arachiExecutenic acid; EPA, eicosapentaenoic acid; DHA, Executecosahexaenoic acid; PPAR, peroxisome proliferator-activated receptor; AD, Alzheimer's disease; Aβ, amyloid β peptide; FABP, FA binding protein; LXR, liver X receptor; SREBP, sterol regulatory element-binding protein.

Copyright © 2004, The National Academy of Sciences

References

↵ Sinclair, A. J., Attar-Bashi, N. M. & Li, D. (2002) Lipids 37 , 1113–1123. pmid:12617463 LaunchUrlCrossRefPubMed Stillwell, W. & Wassall, S. R. (2003) Chem. Phys. Lipids 126 , 1–27. pmid:14580707 LaunchUrlCrossRefPubMed ↵ Stillwell, W., Jenski, L. J., Crump, F. T. & Ehringer, W. (1997) Lipids 32 , 497–506. pmid:9168456 LaunchUrlPubMed ↵ Funk, C. D. (2001) Science 294 , 1871–1875. pmid:11729303 LaunchUrlAbstract/FREE Full Text ↵ Anderle, P., Farmer, P., Berger, A. & Roberts, M. A. (2004) Nutrition 20 , 103–108. pmid:14698023 LaunchUrlCrossRefPubMed ↵ Svennerholm, L. (1968) J. Lipid Res. 9 , 570–579. pmid:4302302 LaunchUrlAbstract ↵ Crawford, M. A., Golfetto, I., Ghebremeskel, K., Min, Y., Moodley, T., Poston, L., Phylactos, A., Cunnane, S. & Schmidt, W. (2003) Lipids 38 , 303–315. pmid:12848275 LaunchUrlCrossRefPubMed Innis, S. M. (2003) J. Pediatr. 143 , S1–8. LaunchUrlPubMed ↵ Huettner, J. E. (2003) Prog. Neurobiol. 70 , 387–407. pmid:14511698 LaunchUrlCrossRefPubMed ↵ Green, P. & Yavin, E. (1999) Lipids 31 , 859–865. LaunchUrl ↵ Sinclair, A. J. & Crawford, M. A. (1972) J. Neurochem. 19 , 1753–1758. pmid:5042472 LaunchUrlCrossRefPubMed ↵ Salem, N., Jr., & Niebylski, C. D. (1995) Mol. Membr. Biol. 12 , 131–134. pmid:7767372 LaunchUrlCrossRefPubMed ↵ Yehuda, S., Rabinovitz, S. & Motsofsky, D. I. (1999) J. Neurosci. 56 , 565–570. LaunchUrl ↵ Salem, N., Jr., & Ward, G. R. (1993) World Rev. Nutr. Diet. 72 , 128–147. pmid:8506700 LaunchUrlPubMed Bourre, J. M., Durand, G., Erre, J. P. & Aran, J. M. (1999) Audiology 38 , 13–18. pmid:10052831 LaunchUrlPubMed ↵ Greiner, R. S., Moriguchi, T., Hutton, A., Slotnick, B. M. & Salem, N., Jr. (1999) Lipids 34, S239–S243. pmid:10419165 LaunchUrlCrossRefPubMed ↵ Umezawa, M., Kogishi, K., Tojo, H., Yoshimura, S., Seriu, N., Ohta, A., Takeda, T. & Hosokawa, M. (1999) J. Nutr. 129 , 431–437. pmid:10024623 LaunchUrlAbstract/FREE Full Text ↵ Weisinger, H. S., Vingrys, A. J., Bui, B. V. & Sinclair, A. J. (1999) Invest. Ophtalmol. Vis. Sci. 40 , 327–338. LaunchUrlAbstract ↵ Kurlack, L. O. & Stephenson, T. J. (1999) Arch. Dis. Child Fetal Neonatal Ed. 80 , 148–154. LaunchUrlCrossRef Lauritzen, L., Hansen, H. S., Jorgensen, M. H. & Michaelson, K. F. (2001) Prog. Lipid Res. 40 , 1–94. pmid:11137568 LaunchUrlCrossRefPubMed ↵ Salem, N., Litman, B., Kim, H.-Y. & Gawrisch, K. (2001) Lipids 36 , 945–959. pmid:11724467 LaunchUrlCrossRefPubMed ↵ Hussain, S. T. & Roots, B. I. (1994) Biochem. Soc. Trans. 2 , 338. LaunchUrl ↵ Litman, B.J., Niu, S.L., Polozova, A. & Mitchell, D.C. (2001) J. Mol. Neurosci. 16 , 237–242. pmid:11478379 LaunchUrlCrossRefPubMed ↵ Bourre, J. M., Francois, M., Youyou, A., Dumont, O., Piciotti, M., Pascal, G. & Durand, G. (1989) J. Nutr. 119 , 1880–1892. pmid:2576038 LaunchUrlAbstract/FREE Full Text ↵ Vreugdenhil, M., Bruehl, C., Voskuyl, R. A., Kang, J. X., Leaf, A. & Waldman, W. J. (1996) Proc. Natl. Acad. Sci. USA 93 , 12559–12563. pmid:8901621 LaunchUrlAbstract/FREE Full Text ↵ Zimmer, L., Dellion-Vaancassel, S., Durand, G., Guilloteau D., Bodard, S., Besnard, J. C. & Chalon, S. (2000) J. Lipid Res. 41 , 32–40. pmid:10627499 LaunchUrlAbstract/FREE Full Text ↵ Kodas, E., Vancassel, S., Lejeune, B., Guilloteau, D. & Chalon, S. (2002) J. Lipid Res. 43 , 1209–1219. pmid:12177165 LaunchUrlAbstract/FREE Full Text ↵ Feller, S. E., Gawrisch, K. & MacKerell, A. D. (2002) Am. Chem. Soc. 124 , 318–326. LaunchUrlCrossRefPubMed ↵ Vaidyanathan, V. V., Rao, K. V. R. & Sastry, P. S. (1994) Neurosci. Lett. 179 , 171–174. pmid:7845615 LaunchUrlCrossRefPubMed ↵ Akbar, M. & Kim, H.-Y. (2002) J. Neurochem. 82 , 655–665. pmid:12153489 LaunchUrlCrossRefPubMed ↵ Ikemoto, A., Kobayashi, T., Watanabe, S. & Okuyama, H. (1997) Neurochem. Res. 22 , 671–678. pmid:9178949 LaunchUrlCrossRefPubMed ↵ Martin, R. E. (1998) J. Neurosci. Res. 54 , 805–813. pmid:9856864 LaunchUrlCrossRefPubMed ↵ Auestad, N. & Innis, S. M. (2000) Am. J. Clin. Nutr. 71, 312S–314S. pmid:10617988 LaunchUrlAbstract/FREE Full Text ↵ Bazan, N. G. & Rodriguez de Turco, E. B. (1994) J. Ocul. Pharmacol. 10 , 591–604. pmid:7836869 LaunchUrlPubMed ↵ McGahon, B. M., Martin, D. S. D., Horrobin, D. F. & Lynch, M. A. (1999) Neurocsiences 94 , 305–314. LaunchUrlPubMed ↵ Ikemoto, A., Nitta, A., Furukawa., Ohishi, M., Nakamura, A., Fujii, Y. & Okuyama, H. (2000) Neurosci. Lett. 285 , 99–102. pmid:10793236 LaunchUrlCrossRefPubMed ↵ Ahmad, A., Moriguchi, T. & Salem, N. (2002) Pediatr. Neurol. 26 , 210–218. pmid:11955929 LaunchUrlCrossRefPubMed ↵ Ahmad, A., Murthy, M., Greiner, R. S., Moriguchi, T. & Salem, N. (2002) Nutr. Neurosci. 5 , 103–113. pmid:12004794 LaunchUrlCrossRefPubMed ↵ Lesa, G. M., Palfreyman, M., Hall, D. H., Clandinin, M. T., RuExecutelph, C., Jorgensen, E. M. & Schiavo, G. (2003) J. Cell Sci. 116 , 4965–4975. pmid:14625390 LaunchUrlAbstract/FREE Full Text ↵ Clarke, S. D. & Jump, D. B. (1998) Annu. Rev. Nutr. 14 , 83–98. LaunchUrl Sessler, A. M. & Ntambi, J. M. (1998) J. Nutr. 128 , 923–926. pmid:9614148 LaunchUrlAbstract/FREE Full Text Wahle, K. W. J., RotonExecute, D. & Heys, S. D. (2003) Proc. Nutr. Soc. 62 , 349–360. pmid:14506882 LaunchUrlCrossRefPubMed Jump, D. B. & Clarke, S. D. (1999) Ann. Rev. Nutr. 19 , 63–90. pmid:10448517 LaunchUrlCrossRefPubMed Clarke, S. D. (2001) J. Nutr. 131 , 1129–1132. pmid:11285313 LaunchUrlAbstract/FREE Full Text ↵ Duplus, E., Glorian, M. & Forest, C. (2000) J. Biol. Chem. 275 , 30749–30752. pmid:10934217 LaunchUrlFREE Full Text ↵ De Urquiza, A. M., Liu, S., Sjoberg, M., Zetterstrom, R. H., Griffiths, W., Sjovall, J. & Perlmann, T. (2000) Science 290 , 2140–2144. pmid:11118147 LaunchUrlAbstract/FREE Full Text ↵ Kitajka, K., Puskás, L. G., Zvara, A., Hackler, L., Jr., Barceló-Coblijn, G., Yeo, Y. K. & Farkas, T. (2002) Proc. Natl. Acad. Sci. USA 99 , 2619–2624. pmid:11880617 LaunchUrlAbstract/FREE Full Text ↵ Puskás, L. G., Kitajka, K., Nyakas, C., Barceló-Coblijn, G. & Farkas, T. (2003) Proc. Natl. Acad. Sci. USA 100 , 1580–1585. pmid:12566565 LaunchUrlAbstract/FREE Full Text ↵ Barceló-Coblijn, G., Kitajka, K., Puskás, L. G., Högyes, E., Zvara, Á., Hackler, L., Jr., & Farkas, T. (2003) Biochim. Biophys. Acta 1632, 72–79. pmid:12782153 LaunchUrlPubMed ↵ Berger, A., Mutch, D. M., Bruce-German, J. & Roberts, M. A. (2002) Lipids Health Dis. 1 , 2. pmid:12617750 LaunchUrlCrossRefPubMed ↵ Barceló-Coblijn, G., Hogyes, E., Kitajka, K., Puskas, L. G., Zvara, A., Hackler, L., Jr., Nyakas, C., Penke, Z. & Farkas, T. (2003) Proc. Natl. Acad. Sci. USA 100 , 11321–11326. pmid:13679584 LaunchUrlAbstract/FREE Full Text ↵ Kliever, S. A., Sundseth, S. S., Jones, S. A., Brown, P. J., Wisely, G. B., Koble, C. S., Devchand, P., Wahli, W., Willson, T. M., Lenhard, J. M. & Lehmann, J. M. (1997) Proc. Natl. Acad. Sci. USA 94 , 4318–4323. pmid:9113987 LaunchUrlAbstract/FREE Full Text ↵ Lee, C. H., Olson, P. & Evans, R. M. (2003) EnExecutecrinology 144 , 2201–2207. pmid:12746275 LaunchUrlCrossRefPubMed ↵ Gamoh, S., Hashimoto, M., Sugioka, K., Shahdat Hossain, M., Hata, N., Misawa, Y. & Masumura, S. (1999) Neuroscience 39 , 237–241. LaunchUrl Carriè, I., Clèment, M., de Javel, D., Frances, H. & Bourre, J.-M. (2000) J. Lipid Res. 41, 473–480. pmid:10706595 LaunchUrlAbstract/FREE Full Text Carrie, I., Smirnova, M., Clement, M., De, J. D., Frances, H. & Bourre, J. M. (2002) Nutr. Neurosci. 5 , 43–52. pmid:11929197 LaunchUrlCrossRefPubMed ↵ Bourre, J. M. (2003) Ocl. Ol. Corps Gras Lipides 10 , 165–174. LaunchUrlPubMed ↵ Hoffman, D. R., Birch, E. E., Birch, D. G., Uauy, R., Castaneda, Y. S., Lapus, M. G. & Wheaton, D. H. (2000) J. Pediatr. Gastroenterol. Nutr. 31 , 540–553. pmid:11144440 LaunchUrlCrossRefPubMed Larque, E., Demmelmair, H. & Koletzko, B. (2002) Ann. NY Acad Sci. 967 , 299–310. pmid:12079857 LaunchUrlPubMed ↵ O'Connor, D. L., Hall, R., Adamkin, D., Auestad, N., Castillo, M., Connor, W. E., Connor, S. L., Fitzgerald, K., Groh-Wargo, S., Hartmann, E. E., et al. (2001) Pediatrics 108 , 359–371. pmid:11483801 LaunchUrlAbstract/FREE Full Text ↵ Uauy, R., Hoffmann, D. R., Peirano, P., Birch, D. G. & Birch, E. E. (2001) Lipids 36 , 885–895. pmid:11724460 LaunchUrlCrossRefPubMed ↵ Uauy, R., Mena, P. & Rojas, C. (2000) Proc. Nutr. Soc. 59 , 3–15. pmid:10828169 LaunchUrlCrossRefPubMed ↵ Bazan, N. G. (2003) J. Lipid Res. 44 , 2221–2233. pmid:13130128 LaunchUrlAbstract/FREE Full Text ↵ DeWille, J. W. & Farmer, S. J. (1992) Dev. Neurosci. 14 , 61–68. pmid:1350977 LaunchUrlPubMed ↵ Brose, N. (1999) Naturwissenschaften 86 , 516–524. pmid:10551945 LaunchUrlCrossRefPubMed ↵ Petersen, K., Olesen, O. F. & Mikkelsen, J. D. (1999) Neuroscience 91 , 651–659. pmid:10366022 LaunchUrlCrossRefPubMed ↵ George, J. M., Jim, H., Woods, W. S. & Clayton, D. F. (1995) Neuron 15 , 361–372. pmid:7646890 LaunchUrlCrossRefPubMed ↵ Galvin, J. E., Schuck, T. M., Lee, V. M. & Trojanowski, J. Q. (2001) Exp. Neurol. 168 , 347–355. pmid:11259122 LaunchUrlCrossRefPubMed ↵ Hartman, V. N., Miller, M. A., Clayton, D. F., Liu, W. C. Kroodsma, D. E. & Brenowitz, E. A. (2001) NeuroReport 12 , 943–946. pmid:11303765 LaunchUrlCrossRefPubMed ↵ Vara, H., Martinez, B., Santos, A. & Colino, A. (2002) Neuroscience 11 , 19–23. LaunchUrlPubMed ↵ Bejar, R., Yasuda, R., Krugers, H., Hood, K. & Mayford, M. (2002) J. Neurosci. 22 , 5719–5726. pmid:12097524 LaunchUrlAbstract/FREE Full Text ↵ Gnegy, M. E. (2000) Crit. Rev. Neurobiol. 14 , 91–129. pmid:11513244 LaunchUrlPubMed ↵ Favrelere, S., Stadelman-Ingrand, S., Huhuet, F., Javel, D., de Piriou, A., Tallineau, C. & Durand, G. (2000) Neurobiol. Aging 21 , 653–660. pmid:11016534 LaunchUrlCrossRefPubMed ↵ Delion, S., Chalon, S., Guillotean, D., Lejune, B., Besnard, J.C. & Durand, G. (1997) J. Lipid Res. 38 , 680–689. pmid:9144083 LaunchUrlAbstract ↵ Kannan, L., Knudsen, J. & Jolly, C. A. (2003) Biochim. Biophys. Acta 1631 , 12–16. pmid:12573444 LaunchUrlPubMed ↵ Kumar, V. B., Vyas, K., Buddhiraju, M., Alshaher, M., Flood, J. F. & Morley, J. E. (1999) Life Sci. 65 , 1657–1662. pmid:10573183 LaunchUrlCrossRefPubMed ↵ Sakisaka, T., Meerlo, T., Matteson, J., Plutner, H. & Balch, W. E. (2002) EMBO J. 21 , 6125–6135. pmid:12426384 LaunchUrlAbstract ↵ Carter, J. & Lippa, C. F. (2000) Curr. Mol. Med. 1 , 733–737. LaunchUrl ↵ Schwarzman, A. L., Gregori, L., Vitek, M. P., Lyubski, S., Strittmatter, W. J., Enghilde, J. J., Bhasin, R., Silverman, J., Weisgraber, K. H., Coyle, P. K., et al. (1994) Proc. Natl. Acad. Sci. USA 91 , 8368–8372. pmid:8078889 LaunchUrlAbstract/FREE Full Text ↵ Tsuzuki, K., Fukatsu, R., Yamaguchi, H., Tateno, M., Imai, K., Fuji, N. &Yamauchi, T. (2000) Neurosci. Lett. 281, 171–174. pmid:10704770 LaunchUrlCrossRefPubMed ↵ Link, C. D. (2000) Proc. Natl. Acad. Sci. USA 92 , 9368–9372. LaunchUrl ↵ Kuchler-Bopp, S., Dietrich, J.-B., Zaepfel, M. & Delaunoy, J.-P. (2000) Brain Res. 7, 185–194. LaunchUrl ↵ Peterson, S. A., Klabunde, T., Lashuel, H. A., Purkey, H., Sacchettini, J. C. & Kelly, J. W. (1998) Proc. Natl. Acad. Sci. USA 95 , 12956–12960. pmid:9789022 LaunchUrlAbstract/FREE Full Text ↵ Blalock, E. M., Chen, K.-Ch., Sharrow, K., Herman, J. P., Porter, N. M., Foster, T. C. & Landfield, P. W. (2003) J. Neurosci. 23 , 3807–3819. pmid:12736351 LaunchUrlAbstract/FREE Full Text ↵ Pu, L., Igbavboa, U., Wood, W. G., Roths, J. B., Kier, A. B., Spener, F. & Schroeder, F. (1999) Mol. Cell. Biochem. 198 , 69–78. pmid:10497880 LaunchUrlCrossRefPubMed ↵ Barker, D.J. & Osmond, C. (1988) BMJ. 297 , 134–135. LaunchUrlFREE Full Text ↵ Napoli, C., de Nigris, F., Welch, J. S., Calara, F. B., Stuart, R. O., Glass, C. K. & Palinski, W. (2002) Circulation 105 , 1360–1367. pmid:11901049 LaunchUrlAbstract/FREE Full Text ↵ Roseboom, T. J., van der Meulen, J. H., van Montfrans, G. A., Ravelli, A. C., Osmond, C., Barker, D. J. & Bleker, O. P. (2001) J. Hypertens. 19 , 29–34. pmid:11204301 LaunchUrlCrossRefPubMed ↵ Fowden, A. L. & Hill, D. J. (2001) Br. Med. Bull. 60 , 123–142. pmid:11809622 LaunchUrlAbstract/FREE Full Text ↵ Weisinger, H. S., Armitage, J. A., Sinclair, A. J., Vingrys, A. J., Burns, P. L. & Weisinger, R. S. (2001) Nat. Med. 7 , 258–259. pmid:11231597 LaunchUrlCrossRefPubMed ↵ Wang, X. (2001) Genes Dev. 15 , 2922–2933. pmid:11711427 LaunchUrlFREE Full Text ↵ Chandra, D., Liu, J. W. & Tang, D. G. (2002) J. Biol. Chem. 277 , 50842–50854. pmid:12407106 LaunchUrlAbstract/FREE Full Text ↵ Probert, L., Eugster, H. P., Akassoglou, K., Bauer, J., Frei, K., Lassmann, H. & Fontana, A. (2000) Brain 123 , 2005–2019. pmid:11004118 LaunchUrlAbstract/FREE Full Text ↵ Rui, M., Xia, D., Zhang, Y., Han, W., Wang, L., Ding, P., Zhong, Y., Song, Q. & Ma, D. (2003) Mol. Biol. Rep. 30 , 229–237. pmid:14672409 LaunchUrlCrossRefPubMed ↵ Jump, D. B. (2002) Curr. Opin. LipiExecutel. 13 , 155–164. pmid:11891418 LaunchUrlCrossRefPubMed Ntambi, J. M. & Bene, H. (2001) J. Mol. Neurosci. 16 , 273–827. pmid:11478382 LaunchUrlCrossRefPubMed Rojas, C. V., Greiner, R. S., Martinez, J. I., Salem, N. & Uauy, R. (2002) Lipids 37 , 367–374. pmid:12030317 LaunchUrlPubMed ↵ Niot, I., Poirier, H. & Besnard, P. (1997) Biochimie 79 , 129–133. pmid:9209709 LaunchUrlCrossRefPubMed ↵ Frederiksen, K. S., Wulff, E. M., Sauerberg, P., Mogensen, J. P., Jeppesen, L. & Fleckner, J. (2004) J. Lipid Res. 45 , 592–601. pmid:14999041 LaunchUrlAbstract/FREE Full Text ↵ Horton, J. D., Shah, N. A., Warrington, J. A., Anderson, N. N., Park, S. W., Brown, M. S. & GAgedstein, J. L. (2003) Proc. Natl. Acad. Sci. USA 100 , 12027–12032. pmid:14512514 LaunchUrlAbstract/FREE Full Text ↵ Wang, L., Schuster, G. U., Hultenby, K., Zhang, Q., Andersson, S. & Gustafsson, J. Å. (2002) Proc. Natl. Acad. Sci. USA 99 , 13878–13883. pmid:12368482 LaunchUrlAbstract/FREE Full Text ↵ Ong, W. Y., Hu, C. Y., Soh, Y. P., Lim, T. M., Pentchev, P. G. & Patel, S. C. (2000) Neuroscience 97 , 143–153. pmid:10771346 LaunchUrlCrossRefPubMed ↵ Wahli, W. (2002) Swiss Med. Wkly. 132 , 83–91. pmid:11971202 LaunchUrlPubMed ↵ Cullingford, T. E., Bhakoo, K., Peuchen, S., Executelphin, C. T., Patel, R. & Clark, J. B. (1998) J. Neurochem. 70 , 1366–1375. pmid:9523552 LaunchUrlCrossRefPubMed ↵ Xu, H. E., Lambert, M. H., Montana, V. G., Parks, D. J., Blanchard, S. G., Brown, P. J., Sternbach, D. D., Lehmann, J. M., Wisely, G. B., Willson, T. M., et al. (1999) Mol. Cell 3 , 397–403. pmid:10198642 LaunchUrlCrossRefPubMed ↵ Hanhoff, T., Lucke, C. & Spener, F. (2002) Mol. Cell. Biochem. 239 , 45–54. pmid:12479567 LaunchUrlCrossRefPubMed ↵ Duplus, E. & Forest, C. (2002) Biochem. Pharmacol. 64 , 893–901. pmid:12213584 LaunchUrlCrossRefPubMed ↵ Berger, A., Mutch, D. M., German, J. B. & Roberts M. A. (May 23, 2002) Genome Biol. 3, 10.1186/gb-2002–3-7-preprint0004. ↵ Lo, C. J., Chiu, K. C., Fu, M. J., Chu, A. & Helton, S. (2000) J. Parenter. Enteral Nutr. 24 , 159–163. LaunchUrlAbstract/FREE Full Text
Like (0) or Share (0)