| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Report of a Meeting |
1 From the Division of Nutritional Sciences and the Institute for Cellular and Molecular Biology, The University of Texas at Austin.
2 Presented at the workshop Role of Nutrient Regulation of Signal Transduction in Metabolic Diseases organized by the National Institutes of Health Nutrition Study Section.
3 Supported by NIH DK 46363 (to SDC) and the American Diabetes Association (SDC). RAB was the recipient of a postdoctoral traineeship (NIH DK 07658).
4 Address reprint requests to SD Clarke, 115 GEA, Department of Human Ecology, The University of Texas at Austin, Austin, TX 78712. E-mail: stevedclarke{at}mail.utexas.edu.
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
, PPAR
, PPAR
1, and PPAR2. These PPARs are related to the T3 and vitamin D3 receptors and bind to a hexameric direct repeat as a heterodimeric complex with retinoid receptor X. PPARs regulate the expression of a wide array of genes that encode proteins involved in lipid metabolism, energy balance, eicosanoid signaling, cell differentiation, and tumorigenesis. A unique feature of these steroid-like receptors is that the physiologic ligands for PPARs appear to be fatty acids from the n-6 and n-3 families of fatty acids and their respective eicosanoid products. This review describes the characteristics, regulation, and gene targets for PPARs and relates their effects on gene expression to physiologic outcomes that affect lipid and glucose metabolism, thermogenesis, atherosclerosis, and cell differentiation.
Key Words: Peroxisome proliferator-activated receptor • fat cells • differentiation • fatty acids • fatty acid synthase • transcription factor • retinoid receptor X • review
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
One dietary constituent that clearly modifies the differentiation, growth, and metabolism of cells is dietary fat. Not only does the amount of fat in the diet influence the development of nutritionally related pathophysiologies such as cancer, but the type of dietary fat has particular effects on cellular functions. For example, the ingestion of a diet high in saturated fat leads to insulin resistance, whereas the consumption of fat rich in 20-carbon and 22-carbon n-3 polyunsaturated fatty acids (PUFAs) normalizes insulin sensitivity (1). The regulation of cell functions by dietary fats can occur on 2 general levels: modulation of signal transduction via manipulation of membrane fatty acid composition (2) and rapid and direct modification of gene transcription (3). The role that membrane phospholipid fatty acid composition plays in hormonal signaling and receptor activity has been extensively pursued over the past 50 y. However, the notion that lipids may govern gene expression by functioning as ligand activators for a wide array of nuclear transcription factors has emerged only in the past few years (3, 4). Thus, this review focuses on the concept that lipids, notably PUFAs and their eicosanoid products, modulate gene transcription by governing the DNA binding activity of specific transcription factors.
|
IDENTIFICATION AND CHARACTERIZATION OF PPARs |
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
(PPAR).
The predicted amino acid sequence for PPAR indicates that this receptor possesses structural features characteristic of steroid receptors, ie, a ligand binding domain and a zinc-finger DNA binding domain (13, 14). Moreover, characterization of the DNA recognition sequence in the 5'-flanking region of the peroxisomal acyl-CoA oxidase gene indicated that PPAR forms a heterodimer partnership with retinoid receptor X (RXR) and that the DNA recognition sequence for the dimer involves 2 direct-repeat half-sites with the consensus hexameric sequence AGGTCA (14). The direct-repeat motif of AGGTCA is identical to the repeat sequence recognized by the T3 and vitamin D3 receptors and by several orphan receptors such as apolipoprotein A-I regulatory protein 1, chicken ovalbumin protein transcription factor, and steroidogenic factor (14–17). In the PPAR response element, however, only 1 nucleotide separates the 5'-AGGTCA RXR binding site from the 3' PPAR binding site (18, 19), whereas there is a 4-nucleotide spacer between the RXR binding site and the binding site for T3 and a 5-nucleotide spacer between the RXR binding site and the binding site for vitamin D3 (19). These early studies revealed that PPAR is a member of the steroid receptor family and that the binding of PPAR to its response element depends on ligand activation of PPAR and the nucleotide spacing between the repeat hexamer. Since the initial identification of PPAR, several PPAR family members have been cloned. These include PPAR1, PPAR2, PPAR (NUC-1/FAAR), and 2 related lipid-activated transcription factors, liver X receptor and farnesoid X receptor (20–24). Numerous studies conducted in the past 5 y indicate that lipid activation of PPARs results in a wide array of cellular changes, including the up-regulation of lipid oxidation, the enhanced expression of certain cell surface receptors, the acceleration of leukotriene degradation, and the stimulation of cell differentiation events.
|
ROLE OF RXR IN THE ACTIONS OF PPARs
|
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
(14, 18–20). An example of the importance of RXR to PPAR regulation of gene expression is particularly evident in differentiating 3T3-L1 preadipocytes (25). Although these preadipocytes contain ample amounts of PPAR, PPAR will not bind to the PPAR response element nor will it stimulate the transcription of genes encoding proteins involved in terminal fat cell differentiation (eg, adipose fatty acid binding protein) until RXR synthesis is stimulated by adding dexamethasone to the media (25). PPAR response element binding by the PPAR-RXR heterodimer requires the presence of both proteins, and the DNA interaction is greatly enhanced by the binding of ligands to RXR (eg, 9-cis retinoic acid) and to PPAR partners (eg, thiazolidenediones) (25–27).
Because all PPAR family members form heterodimer complexes with RXR, and because these heterodimer complexes bind to the same PPAR response element, it is not surprising to find that PPARs compete with each other for their RXR partner and subsequent binding to the hexameric repeat recognition sequence (27). Given such competition, how then do PPARs target specific genes? The answer to this question is that selection of the appropriate gene target and PPAR partner is determined by the type and amount of PPAR within a cell, the type of ligand signal, the extent of phosphorylation of PPAR, and the type of competition that may exist among other steroid receptor family members (26–36). With respect to competition among steroid receptor family members, RXR is not only the partner for PPARs but is also the heterodimer partner for T3 and vitamin D3 receptors (27). More importantly, recent evidence indicates that the partners for RXR compete for dimerization (20, 27–31). As an example of such competition, Chu et al (30) found that T3 activation of the T3 receptor attenuated the PPAR signal by reducing the availability of RXR for binding to PPAR. They also found that over-expressing PPAR impaired T3 signaling by depriving the T3 receptor of RXR (30). Ren et al (20) also reported that ligand activation of PPAR in isolated hepatocytes inhibited S14 (a putative lipogenic gene) gene expression by interfering with the formation of the T3-RXR heterodimer complex (20).
Because PUFAs are ligands for PPAR, these data suggest that PUFAs may modulate the expression of T3-responsive genes (eg, S14 and fatty acid synthase) by activating PPAR and interfering with T3-RXR binding activity. Such an observation may explain the early observations that dietary PUFAs reduce the hepatic responsiveness of lipogenic genes to T3 (10). However, note that in addition to a possible interaction between PPAR and T3, PUFAs also regulate lipogenic genes by a mechanism that is independent of their role as a PPAR ligand (3, 12). Clearly, the regulation of gene transcription by PPAR ligands has several levels of complexity that go beyond the simple identification of cis elements and trans factors.
|
LIGAND ACTIVATORS OF PPARs AND THEIR PHYSIOLOGIC CONSEQUENCES |
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
The finding that polyenoic fatty acids are more potent activators of PPARs than are saturated and monounsaturated fatty acids parallels the metabolic findings that n-6 and n-3 PUFAs are more potent inducers of fatty acid oxidation and more potent suppressers of fatty acid and triacylglycerol synthesis (5, 6, 10, 11, 37–40). This correlation has led to the proposal that PPARs coordinately regulate the expression of genes involved in the oxidation and synthesis of lipids. Numerous reports over the past 5 y have in fact unequivocally established that the 5' flanking regions of genes encoding carnitine O-palmitoyltransferase, acyl-CoA oxidase, mitochondrial hydroxymethylglutaryl-CoA synthase, fatty-acyl-CoA synthetase, and mitochondrial uncoupling proteins all contain DNA recognition sequences for PPAR (37–43). Moreover, dietary studies revealed that feeding a diet rich in 20-carbon and 22-carbon PUFAs (ie, PPAR ligand activators) significantly increases the expression of the aforementioned genes and that induction of these genes is associated with higher rates of fat oxidation and reduced body fat deposition (37–42). The pivotal role that PPAR plays in energy balance is convincingly supported by the recent report that transgenic mice deficient in PPAR display a maturity onset obesity and hypertriglyceridemia in the absence of hyperphagia (43). There appears to be little question that PPARs play a key role in lipid oxidation and energy balance, but numerous studies have failed to show that PPARs participate directly in the PUFA suppression of lipogenic and glycolytic genes. This indicates that fatty acids regulate gene transcription by 2 independent mechanisms, only one of which is dependent on PPAR.
Eicosanoid activators and cell differentiation
Transcription activation assays and gel shift studies indicate that in addition to fatty acids, eicosanoid products of cyclooxygenase and lipoxygenase are potent ligand activators of PPARs (44–48). As for fatty acid ligands, the activation potency of eicosanoids varies with type (36, 45, 46). This discovery that eicosanoids are ligand activators of nuclear transcription factors adds a new dimension to eicosanoid signaling.
Examples of eicosanoid ligands for PPARs are leukotriene B4 and 8S-hydroxyeicosatetraenoic acid (44). Leukotriene B4 is a strong chemotactic agent of inflammation that is synthesized by immune cells but degraded primarily by the liver (44). In ligand activation assays, leukotriene B4 activates hepatocyte PPAR, PPAR, and PPAR (44), and the response of PPAR to leukotriene B4 is 25–30-fold greater than that of the other PPARs (44). Because leukotriene B4 is degraded by enzymes of the peroxisomes, activation of PPAR up-regulates the peroxisomal enzymes of leukotriene degradation and in this way governs the amplitude of the inflammatory signal (44). Eicosanoid activation of PPARs also appears to be a key mechanism by which prostaglandins govern the expression of genes involved in cellular differentiation (35, 45–48). For example, the binding and activation of PPAR2 by 15-deoxy-12,14-prostaglandin J2 (15-deoxy-12,14-PG-J2) induces the expression of genes (eg, fatty acid binding protein and lipoprotein lipase) involved in the terminal differentiation of fat cells (46). Similarly, fatty acid activation of PPAR (ie, NUC-1) reportedly stimulates human osteosarcoma cells to differentiate (35). PG-A1, PG-D2, and PG-J2 reportedly exert antitumor effects on human cancer cells, including those derived from melanoma, leukemia, and ovarian carcinoma (47). Like fatty acid ligands, the potency for prostanoid activation of PPARs varies with the type of prostaglandin and the type of PPAR. For example, PPAR, which is relatively insensitive to fatty acid activation, is activated 80–90-fold by PG-D1 and PG-D2 (46).
Clearly, n-6 and n-3 PUFAs and their respective eicosanoid products have marked effects on cellular metabolism and cellular differentiation. Elucidation of the mechanisms of these effects will contribute significantly to our understanding of how dietary fats are related to the development and prevention of nutritionally related pathophysiologies. It will be interesting to ascertain whether n-6 and n-3 PUFAs and their respective eicosanoid products exert different effects on gene expression and events of cell differentiation by functioning as competitive ligands for PPARs.
Thiazolidenedione activators of PPAR and diabetes
In light of the observation that PPARs play a central role in cellular metabolism and differentiation, a significant effort has been underway to identify specific PPAR ligands with pharmacologic benefits (49–52). One of the most productive areas of research has been in the discovery and use of thiazolidenediones (49–52). Thiazolidenediones (eg, pioglitazone and troglitazone) are orally active insulin-sensitizing agents that appear to exert their effects by functioning as PPAR activators (49–52). Adipose tissue and skeletal muscle appear to be the key targets for thiazolidenediones (52–55). Thiazolidenedione activation of PPAR in adipose tissue accelerates the rate of fat cell differentiation, which is accompanied by an increase in cell number and an increase in the expression of glucose transporter 4, fatty acid binding protein, and lipoprotein lipase (49–53). Thiazolidenedione activation of PPAR in skeletal muscle is associated with increased expression of lipoprotein lipase and glucose transporter 4 (52, 53). The collective outcome of these genomic responses is improved insulin sensitivity, enhanced glucose metabolism, and decreased blood triacylglycerol concentrations (49–53). Current efforts to identify potent ligand activators of PPARs may soon lead to the identification of factors that regulate tumor growth and inflammatory response.
PPAR involvement in atherosclerosis
Although PPAR activators have been found to exert several beneficial influences, not all outcomes of PPAR activation are beneficial (4, 56). For example, fibrates, which are ligands for PPAR and thereby function to enhance the expression of genes encoding proteins of lipid oxidation, also stimulate the production of apolipoprotein (apo) A-I and A-II (4). Unfortunately, apo A-II synthesis is stimulated to a greater extent than is apo A-I synthesis (4). The result is the formation of a less desirable HDL particle that contains a lower ratio of apo A-I to A-II (4). However, part of this detrimental outcome of fibrate activation of PPAR is offset by an apparent PPAR-dependent increase in the expression of lipoprotein lipase and a parallel decrease in apo C-III production (4).
In addition to the effect that fibrates may exert on apo profiles, recent evidence strongly indicates that the induction and activation of PPAR by oxidized LDL is a key component in the formation of foam cells from monocytes (56). In the development of an atherosclerotic plaque, monocytes migrate into the subendothelial space and rapidly accumulate lipid. These monocytes give rise to lipid-laden foam cells characteristic of an atherosclerotic plaque. Tontonoz et al (56) showed recently that treating monocytes with oxidized LDL causes a rapid and extensive increase in the expression of PPAR. Moreover, ligand activation (presumably oxidized fatty acid) of the PPAR enhanced the expression of the scavenger receptor CD36, which in turn was associated with enhanced uptake of LDL cholesterol (56). This exquisitely conducted study not only shows that PPAR activators play a role in the development of nutritionally related pathophysiologies (eg, atherosclerosis), but also suggests that PPAR antagonists may have pharmacologic benefits (much like PPAR2 agonists, which have improved the treatment of insulin resistance).
|
ROLE OF PHOSPHORYLATION IN PPAR ACTION |
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
and PPAR, but also increases the tyrosine phosphorylation of extracellular-signal-regulated kinase (ERK)-1 and ERK-2, which in turn induce the transcription of several immediate-early genes (58). Activation of the ERK–mitogen-activated protein kinase (MAPK) cascade also appears to increase the phosphorylation state of certain PPARs, which in turn alters their DNA binding activity (57–60). As an example, insulin treatment of adipocytes and CV-1 cells increases the phosphorylation of PPAR by 3-fold within 30 min (59). Moreover, the increase in PPAR phosphorylation is associated with a 2-fold increase in the transcriptional activity of PPAR (59). Similarly, insulin activation of the MAPK cascade in adipocytes enhances the transcriptional activity of PPAR1 and PPAR2 (59). Mutation analysis revealed that the activation domain within PPAR is located in the amino terminal, ligand-independent region of the protein (59). In contrast with these findings, Adams et al (61) reported that MAPK phosphorylation of PPAR inhibits both ligand-independent and ligand-dependent trans-activation functions of PPAR, which in turn is associated with a suppression of fat cell differentiation (61). Collectively, the available data indicate that PPARs undergo phosphorylation and dephosphorylation, but the effect of this on PPAR binding to its DNA recognition sequence and on gene transcription and cell differentiation remains to be determined. |
IS THE PUFA REGULATION OF LIPOGENESIS A PPAR-REGULATED PROCESS? |
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
2-regulated genes. Rather, we are discussing the role that PUFAs play in suppressing the fatty acid biosynthetic pathway of liver and possibly skeletal muscle.
The first evidence suggesting that PPARs may not mediate the PUFA control of lipogenic gene expression was derived from ligand activation assays designed to identify PPAR ligand activators (32). In these assays, saturated fatty acids had nearly the same ligand activation capability as PUFAs. For example, 12:0 was nearly as potent as 18:2n-6 as an activator of PPAR, and 18:1n-9 was nearly equivalent to 18:2n-6 as an activator of PPAR, but only 18:2n-6 was found to inhibit hepatic lipogenic gene expression (33). Second, a PUFA response region (PUFA response element) was located in the proximal promoter of the pyruvate kinase and S14 genes (65, 66). However, this DNA sequence does not correspond to a characteristic PPAR response sequence nor does it bind PPAR (64). A third piece of data arguing against a role for PPAR in the PUFA regulation of lipogenic gene transcription is derived from in vivo studies using the potent PPAR activator eicosatetraynoic acid (ETYA) (11, 12). When ETYA is fed to mice, it induces the expression of hepatic acyl-CoA oxidase as expected (12). However, ETYA has no inhibitory effect on hepatic fatty acid synthase expression (12). In fact, ETYA prevents 18:2n-6 from inhibiting fatty acid synthase gene transcription (12, 40). Similarly, treating cultured hepatocytes with 20:4n-6 suppresses fatty acid synthase promoter activity, but treating the hepatocytes with the potent PPAR activator Wy 14643, or with activators for PPAR and PPAR (eg, PG-J2 and pioglitazone), has no effect on hepatocyte fatty acid synthase expression (MG Teran and SD Clarke, unpublished observations, 1998). Perhaps the most convincing data against the idea that PPARs coordinately regulate genes involved in lipid oxidation and synthesis come from the observation that PUFAs continue to suppress fatty acid synthase and S14 gene transcription in the PPAR knockout mouse, but PUFAs fail to induce the expression of peroxisomal acyl-CoA oxidase (63). Collectively, these data indicate that there appear to be 2 independent mechanisms by which fatty acids, particularly PUFAs, regulate gene expression and cell functions. The first of these involves the lipid activation of a steroid-type receptor termed PPAR; the second mechanism, which targets the pathways of glycolysis and fatty acid biosynthesis, remains to be elucidated.
|
SUMMARY |
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
in liver and skeletal muscle leads to the increased expression of genes encoding enzymes of fatty acid oxidation, which appears to be associated with decreased body fat deposition and increased whole-body thermogenesis. Leukotriene activation of hepatic PPAR may be responsible for attenuating inflammatory signals. PPAR binding of PUFAs and their eicosanoid products induces changes in cell differentiation that may result in both beneficial and detrimental outcomes. For example, oxidized LDL appears to enhance PPAR activity in monocytes and this in turn leads to foam cell formation and possibly atherosclerosis. On the other hand, prostanoid activation of PPAR in melanoma and leukemia cells reportedly exerts an antitumor effect. Such changes in cell metabolism and differentiation elicited by fatty acid activation of PPARs provide nuclear targets for elucidating the role that dietary fats play in the development of nutritionally related pathophysiologies. Moreover, although much attention has been paid to the identification of physiologic ligand agonists for PPARs, there is undoubtedly much to be gained from pursuing the identification of dietary antagonists for these influential trans-factors. |
ACKNOWLEDGMENTS |
|---|
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONIDENTIFICATION AND...ROLE OF RXR{alpha} IN...LIGAND ACTIVATORS OF PPARs...ROLE OF PHOSPHORYLATION IN...IS THE PUFA REGULATION...SUMMARYREFERENCES |
|---|
is activated by inducers of adipogenesis, including thiazolidinedione drugs. Eur J Biochem 1996;239:1–7.[Medline]
-hydroxylase gene (CYP7A). J Biol Chem 1997;272:9833–9.2 versus PPAR1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 1997;272:8071–6. inhibits hepatic S14 gene transcription. J Biol Chem 1996; 271:17167–73.2 in differentiating 3T3-L1 preadipocytes. J Lipid Res 1998;39:2329–38. and . Proc Natl Acad Sci U S A 1997;94:4318–23. and . Proc Natl Acad Sci U S A 1997;94:4312–7.–isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steatosis. J Biol Chem 1998;273:29577–85.-leukotriene B4 pathway to inflammation control. Nature 1996;384:39–43.[Medline]
. Cell 1995;83:803–12.[Medline]
, is aberrantly expressed in colonic cancers. Carcinogenesis 1998;19:49–53. and promotes adipocyte differentiation. Cell 1995;83:813–9.[Medline]
: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology 1996;137:4189–95.[Abstract]
(PPAR). J Biol Chem 1995;270:12953–6. promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 1998;93:241–52.[Medline]
is a phosphoprotein: regulation by insulin. Endocrinology 1996;137:4499–502.[Abstract]
(PPAR). J Biol Chem 1997;272:20230–5.. Science 1996;274:2100–3. is inhibited by phosphorylation at a consensus mitogen activated protein kinase site. J Biol Chem 1997;271:5128–32.
. J Biol Chem 1997;272:26827–32.This article has been cited by other articles:
|
|
 |
|
  P. Nieminen, A.-M. Mustonen, V. Karja, J. Asikainen, and K. Rouvinen-Watt Fatty Acid Composition and Development of Hepatic Lipidosis During Food Deprivation--Mustelids as a Potential Animal Model for Liver Steatosis Experimental Biology and Medicine, March 1, 2009; 234(3): 278 - 286. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ulrich, S. M. Loitsch, O. Rau, A. von Knethen, B. Brune, M. Schubert-Zsilavecz, and J. M. Stein Peroxisome Proliferator-Activated Receptor {gamma} as a Molecular Target of Resveratrol-Induced Modulation of Polyamine Metabolism. Cancer Res., July 15, 2006; 66(14): 7348 - 7354. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Martinsen, I. Bakke, D. Chen, A. K. Sandvik, K. Zahlsen, T. Aamo, and H. L. Waldum Ciprofibrate stimulates the gastrin-producing cell by acting luminally on antral PPAR-{alpha} Am J Physiol Gastrointest Liver Physiol, December 1, 2005; 289(6): G1052 - G1060. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Yin, R. G. Russell, L. E. Dettin, R. Bai, Z.-L. Wei, A. P. Kozikowski, L. Kopleovich, and R. I. Glazer Peroxisome Proliferator-Activated Receptor {delta} and {gamma} Agonists Differentially Alter Tumor Differentiation and Progression during Mammary Carcinogenesis Cancer Res., May 1, 2005; 65(9): 3950 - 3957. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Tai, D. Corella, S. Demissie, L. A. Cupples, O. Coltell, E. J. Schaefer, K. L. Tucker, and J. M. Ordovas Polyunsaturated Fatty Acids Interact with the PPARA-L162V Polymorphism to Affect Plasma Triglyceride and Apolipoprotein C-III Concentrations in the Framingham Heart Study J. Nutr., March 1, 2005; 135(3): 397 - 403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. P. A. Kauwell Emerging Concepts in Nutrigenomics: A Preview of What Is to Come Nutr Clin Pract, February 1, 2005; 20(1): 75 - 87. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. E. Richards, B. Chau, M. R. White, and C. A. McQueen Hepatic Gene Expression and Lipid Homeostasis in C57Bl/6 Mice Exposed to Hydrazine or Acetylhydrazine Toxicol. Sci., November 1, 2004; 82(1): 318 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Tang, H. P. Cho, M. T. Nakamura, and S. D. Clarke Regulation of human {Delta}-6 desaturase gene transcription: identification of a functional direct repeat-1 element J. Lipid Res., April 1, 2003; 44(4): 686 - 695. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Meirhaeghe, L. Fajas, F. Gouilleux, D. Cottel, N. Helbecque, J. Auwerx, and P. Amouyel A Functional Polymorphism in a STAT5B Site of the Human PPAR{gamma}3 Gene Promoter Affects Height and Lipid Metabolism in a French Population Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 289 - 294. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. H. Lee and K. L. Hossner Coordinate regulation of ovine adipose tissue gene expression by propionate J Anim Sci, November 1, 2002; 80(11): 2840 - 2849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Tunstall, K. A. Mehan, G. D. Wadley, G. R. Collier, A. Bonen, M. Hargreaves, and D. Cameron-Smith Exercise training increases lipid metabolism gene expression in human skeletal muscle Am J Physiol Endocrinol Metab, July 1, 2002; 283(1): E66 - E72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Clarke Polyunsaturated Fatty Acid Regulation of Gene Transcription: A Molecular Mechanism to Improve the Metabolic Syndrome J. Nutr., April 1, 2001; 131(4): 1129 - 1132. [Abstract] [Full Text]
|
|
|
|
|
|
M. T. Nakamura, H. P. Cho, and S. D. Clarke Regulation of Hepatic {Delta}-6 Desaturase Expression and Its Role in the Polyunsaturated Fatty Acid Inhibition of Fatty Acid Synthase Gene Expression in Mice J. Nutr., June 1, 2000; 130(6): 1561 - 1565. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. K Kim National Institutes of Health workshop: Role of Nutrient Regulation of Signal Transduction in Metabolic Diseases Am. J. Clinical Nutrition, October 1, 1999; 70(4): 544 - 544. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
