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  1. Article: Modulation of PPARgamma activity with pharmaceutical agents: treatment of insulin resistance and atherosclerosis.

    Wang, Minghan / Tafuri, Sherrie

    Journal of cellular biochemistry

    2003  Volume 89, Issue 1, Page(s) 38–47

    Abstract: The anti-diabetic thiazolidinediones (TZDs) are a class of compounds with insulin-sensitizing activity that were originally discovered using in vivo pharmacological screens. In subsequent binding studies, TZDs were demonstrated to enhance insulin action ... ...

    Abstract The anti-diabetic thiazolidinediones (TZDs) are a class of compounds with insulin-sensitizing activity that were originally discovered using in vivo pharmacological screens. In subsequent binding studies, TZDs were demonstrated to enhance insulin action by activating peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is a member of the ligand-activated nuclear receptor superfamily that promotes adipogenesis and enhances insulin sensitivity by controlling the expression of genes in glucose and lipid metabolism. Given the large size of the ligand binding pocket in PPARgamma, novel classes of both full and partial agonists that are structurally distinct from TZDs have been discovered. These compounds have been effective tools in differentiating adipogenic and insulin-sensitizing activities as well as tissue selectivity of PPARgamma activation. This information has led to the hypothesis that one ligand can activate or inactivate PPARs depending upon the tissue in which the PPAR resides. Thus particular compounds can be designated selective PPAR modulators or SPPARMs, a concept similar to that observed with the activation of estrogen receptor (ER) by SERMS. Additionally, both preclinical and clinical data suggest that PPARgamma activation is useful for the prevention of atherosclerosis. However, the effects of TZDs on plasma lipid profiles do not solely account for their anti-atherogenic effects. Recent studies with macrophage cells and animal models for atherosclerosis indicate that TZDs reduce the size and number of lesions formed in the vessel wall by modulating foam cell formation and inflammatory responses by macrophages. Thus in addition to the treatment of type II diabetes, PPARgamma agonists can be potentially employed for the treatment of atherosclerosis in general population.
    MeSH term(s) Animals ; Arteriosclerosis/drug therapy ; Arteriosclerosis/metabolism ; Diabetes Mellitus, Type 2/drug therapy ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Hypoglycemic Agents/pharmacology ; Insulin Resistance/physiology ; Models, Biological ; Receptors, Cytoplasmic and Nuclear/agonists ; Receptors, Cytoplasmic and Nuclear/metabolism ; Thiazoles/pharmacology ; Thiazolidinediones ; Transcription Factors/agonists ; Transcription Factors/metabolism
    Chemical Substances Hypoglycemic Agents ; Receptors, Cytoplasmic and Nuclear ; Thiazoles ; Thiazolidinediones ; Transcription Factors ; 2,4-thiazolidinedione (AA68LXK93C)
    Language English
    Publishing date 2003-05-01
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 392402-6
    ISSN 1097-4644 ; 0730-2312
    ISSN (online) 1097-4644
    ISSN 0730-2312
    DOI 10.1002/jcb.10492
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Cholesterol and cholate components of an atherogenic diet induce distinct stages of hepatic inflammatory gene expression.

    Vergnes, Laurent / Phan, Jack / Strauss, Merav / Tafuri, Sherrie / Reue, Karen

    The Journal of biological chemistry

    2003  Volume 278, Issue 44, Page(s) 42774–42784

    Abstract: Atherosclerosis in inbred mouse strains has been widely studied by using an atherogenic (Ath) diet containing cholesterol, cholic acid, and fat, but the effect of these components on gene expression has not been systematically examined. We employed DNA ... ...

    Abstract Atherosclerosis in inbred mouse strains has been widely studied by using an atherogenic (Ath) diet containing cholesterol, cholic acid, and fat, but the effect of these components on gene expression has not been systematically examined. We employed DNA microarrays to interrogate gene expression levels in liver of C57BL/6J mice fed the following five diets: mouse chow, the Ath diet, or modified versions of the Ath diet in which either cholesterol, cholate, or fat were omitted. Dietary cholesterol and cholate produced discrete gene expression patterns. Cholesterol was required for induction of genes involved in acute inflammation, including three genes of the serum amyloid A family, three major histocompatibility class II antigen genes, and various cytokine-related genes. In contrast, cholate induced expression of genes involved in extracellular matrix deposition in hepatic fibrosis, including five collagen family members, collagen-interacting proteins, and connective tissue growth factor. The gene expression findings were confirmed by biochemical measurements showing that cholesterol was required for elevation of circulating serum amyloid A, and cholate was required for accumulation of collagen in the liver. The possibility that these gene expression changes are relevant to atherogenesis in C57BL/6J mice was supported by the observation that the closely related, yet atherosclerosis-resistant, C57BL/6ByJ strain was largely resistant to dietary induction of the inflammatory and fibrotic response genes. These results establish that cholesterol and cholate components of the Ath diet have distinct proatherogenic effects on gene expression and suggest a strategy to study the contribution of acute inflammatory response and fibrogenesis independently through dietary manipulation.
    MeSH term(s) Animal Nutritional Physiological Phenomena ; Animals ; Cholates/chemistry ; Cholates/metabolism ; Cholesterol/chemistry ; Cholesterol/metabolism ; Collagen/metabolism ; Diet, Atherogenic ; Extracellular Matrix/metabolism ; Fibrosis ; Gene Expression Regulation ; Inflammation/genetics ; Lipid Metabolism ; Liver/immunology ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Oligonucleotide Array Sequence Analysis ; RNA, Messenger/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Serum Amyloid A Protein/biosynthesis ; Time Factors
    Chemical Substances Cholates ; RNA, Messenger ; Serum Amyloid A Protein ; Collagen (9007-34-5) ; Cholesterol (97C5T2UQ7J)
    Language English
    Publishing date 2003-08-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M306022200
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  3. Article ; Online: The G0/G1 switch gene 2 is a novel PPAR target gene.

    Zandbergen, Fokko / Mandard, Stéphane / Escher, Pascal / Tan, Nguan Soon / Patsouris, David / Jatkoe, Tim / Rojas-Caro, Sandra / Madore, Steve / Wahli, Walter / Tafuri, Sherrie / Müller, Michael / Kersten, Sander

    The Biochemical journal

    2005  Volume 392, Issue Pt 2, Page(s) 313–324

    Abstract: PPARs (peroxisome-proliferator-activated receptors) alpha, beta/delta and gamma are a group of transcription factors that are involved in numerous processes, including lipid metabolism and adipogenesis. By comparing liver mRNAs of wild-type and PPARalpha- ...

    Abstract PPARs (peroxisome-proliferator-activated receptors) alpha, beta/delta and gamma are a group of transcription factors that are involved in numerous processes, including lipid metabolism and adipogenesis. By comparing liver mRNAs of wild-type and PPARalpha-null mice using microarrays, a novel putative target gene of PPARalpha, G0S2 (G0/G1 switch gene 2), was identified. Hepatic expression of G0S2 was up-regulated by fasting and by the PPARalpha agonist Wy14643 in a PPARalpha-dependent manner. Surprisingly, the G0S2 mRNA level was highest in brown and white adipose tissue and was greatly up-regulated during mouse 3T3-L1 and human SGBS (Simpson-Golabi-Behmel syndrome) adipogenesis. Transactivation, gel shift and chromatin immunoprecipitation assays indicated that G0S2 is a direct PPARgamma and probable PPARalpha target gene with a functional PPRE (PPAR-responsive element) in its promoter. Up-regulation of G0S2 mRNA seemed to be specific for adipogenesis, and was not observed during osteogenesis or myogenesis. In 3T3-L1 fibroblasts, expression of G0S2 was associated with growth arrest, which is required for 3T3-L1 adipogenesis. Together, these data indicate that G0S2 is a novel target gene of PPARs that may be involved in adipocyte differentiation.
    MeSH term(s) Adipocytes/cytology ; Adipocytes/metabolism ; Adipogenesis ; Animals ; Base Sequence ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; Cell Line ; Endoplasmic Reticulum/metabolism ; Gene Deletion ; Hepatocytes/cytology ; Hepatocytes/metabolism ; Humans ; Liver/cytology ; Male ; Mice ; Molecular Sequence Data ; Oligonucleotide Array Sequence Analysis ; PPAR alpha/genetics ; PPAR alpha/metabolism ; Promoter Regions, Genetic/genetics ; Protein Transport ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Rats ; Response Elements/genetics ; Sequence Homology, Nucleic Acid ; Substrate Specificity ; Up-Regulation
    Chemical Substances Cell Cycle Proteins ; G0S2 protein, human ; G0S2 protein, mouse ; PPAR alpha ; RNA, Messenger
    Language English
    Publishing date 2005-12-01
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2969-5
    ISSN 1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
    ISSN (online) 1470-8728
    ISSN 0006-2936 ; 0306-3275 ; 0264-6021
    DOI 10.1042/BJ20050636
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    Uc I Zs.110: Show issues Location:
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  4. Article: PPARalpha governs glycerol metabolism.

    Patsouris, David / Mandard, Stéphane / Voshol, Peter J / Escher, Pascal / Tan, Nguan Soon / Havekes, Louis M / Koenig, Wolfgang / März, Winfried / Tafuri, Sherrie / Wahli, Walter / Müller, Michael / Kersten, Sander

    The Journal of clinical investigation

    2004  Volume 114, Issue 1, Page(s) 94–103

    Abstract: Glycerol, a product of adipose tissue lipolysis, is an important substrate for hepatic glucose synthesis. However, little is known about the regulation of hepatic glycerol metabolism. Here we show that several genes involved in the hepatic metabolism of ... ...

    Abstract Glycerol, a product of adipose tissue lipolysis, is an important substrate for hepatic glucose synthesis. However, little is known about the regulation of hepatic glycerol metabolism. Here we show that several genes involved in the hepatic metabolism of glycerol, i.e., cytosolic and mitochondrial glycerol 3-phosphate dehydrogenase (GPDH), glycerol kinase, and glycerol transporters aquaporin 3 and 9, are upregulated by fasting in wild-type mice but not in mice lacking PPARalpha. Furthermore, expression of these genes was induced by the PPARalpha agonist Wy14643 in wild-type but not PPARalpha-null mice. In adipocytes, which express high levels of PPARgamma, expression of cytosolic GPDH was enhanced by PPARgamma and beta/delta agonists, while expression was decreased in PPARgamma(+/-) and PPARbeta/delta(-/-) mice. Transactivation, gel shift, and chromatin immunoprecipitation experiments demonstrated that cytosolic GPDH is a direct PPAR target gene. In line with a stimulating role of PPARalpha in hepatic glycerol utilization, administration of synthetic PPARalpha agonists in mice and humans decreased plasma glycerol. Finally, hepatic glucose production was decreased in PPARalpha-null mice simultaneously fasted and exposed to Wy14643, suggesting that the stimulatory effect of PPARalpha on gluconeogenic gene expression was translated at the functional level. Overall, these data indicate that PPARalpha directly governs glycerol metabolism in liver, whereas PPARgamma regulates glycerol metabolism in adipose tissue.
    MeSH term(s) 3T3 Cells ; Animals ; Base Sequence ; Carcinoma, Hepatocellular ; Cell Line, Tumor ; Cloning, Molecular ; DNA Primers ; Gene Expression Regulation ; Glycerol/metabolism ; Homeostasis ; Humans ; Liver/metabolism ; Liver Neoplasms ; Mice ; Mice, Knockout ; Models, Animal ; Oligonucleotide Array Sequence Analysis ; Plasmids ; Receptors, Cytoplasmic and Nuclear/deficiency ; Receptors, Cytoplasmic and Nuclear/genetics ; Receptors, Cytoplasmic and Nuclear/physiology ; Recombinant Proteins/metabolism ; Transcription Factors/deficiency ; Transcription Factors/genetics ; Transcription Factors/physiology ; Transfection
    Chemical Substances DNA Primers ; Receptors, Cytoplasmic and Nuclear ; Recombinant Proteins ; Transcription Factors ; Glycerol (PDC6A3C0OX)
    Language English
    Publishing date 2004-07
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3067-3
    ISSN 1558-8238 ; 0021-9738
    ISSN (online) 1558-8238
    ISSN 0021-9738
    DOI 10.1172/JCI20468
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    Ua VI Zs.184: Show issues Location:
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  5. Article: Protein kinase A site-specific phosphorylation regulates ATP-binding cassette A1 (ABCA1)-mediated phospholipid efflux.

    See, Raymond H / Caday-Malcolm, Rosalinda A / Singaraja, Roshni R / Zhou, Steven / Silverston, Anthony / Huber, Mary T / Moran, Josh / James, Erick R / Janoo, Rozmin / Savill, Jane M / Rigot, Veronique / Zhang, Lin-Hua / Wang, Minghan / Chimini, Giovanna / Wellington, Cheryl L / Tafuri, Sherrie R / Hayden, Michael R

    The Journal of biological chemistry

    2002  Volume 277, Issue 44, Page(s) 41835–41842

    Abstract: ATP-binding cassette A1 (ABCA1) is a key mediator of cholesterol and phospholipid efflux to apolipoprotein particles. We show that ABCA1 is a constitutively phosphorylated protein in both RAW macrophages and in a human embryonic kidney cell line ... ...

    Abstract ATP-binding cassette A1 (ABCA1) is a key mediator of cholesterol and phospholipid efflux to apolipoprotein particles. We show that ABCA1 is a constitutively phosphorylated protein in both RAW macrophages and in a human embryonic kidney cell line expressing ABCA1. Furthermore, we demonstrate that phosphorylation of ABCA1 is mediated by protein kinase A (PKA) or a PKA-like kinase in vivo. Through site-directed mutagenesis studies of consensus PKA phosphorylation sites and in vitro PKA kinase assays, we show that Ser-1042 and Ser-2054, located in the nucleotide binding domains of ABCA1, are major phosphorylation sites for PKA. ApoA-I-dependent phospholipid efflux was decreased significantly by mutation of Ser-2054 alone and Ser-1042/Ser-2054 but was not significantly impaired with Ser-1042 alone. The mechanism by which ABCA1 phosphorylation affected ApoA-I-dependent phospholipid efflux did not involve either alterations in ApoA-I binding or changes in ABCA1 protein stability. These studies demonstrate a novel serine (Ser-2054) on the ABCA1 protein crucial for PKA phosphorylation and for regulation of ABCA1 transporter activity.
    MeSH term(s) ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/chemistry ; ATP-Binding Cassette Transporters/physiology ; Amino Acid Sequence ; Animals ; Apolipoprotein A-I/metabolism ; Cells, Cultured ; Cyclic AMP-Dependent Protein Kinases/metabolism ; Humans ; Mice ; Molecular Sequence Data ; Phospholipids/metabolism ; Phosphorylation ; Serine ; Structure-Activity Relationship
    Chemical Substances ABCA1 protein, human ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; Apolipoprotein A-I ; Phospholipids ; Serine (452VLY9402) ; Cyclic AMP-Dependent Protein Kinases (EC 2.7.11.11)
    Language English
    Publishing date 2002-08-23
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1074/jbc.M204923200
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Truncation mutations in ABCA1 suppress normal upregulation of full-length ABCA1 by 9-cis-retinoic acid and 22-R-hydroxycholesterol.

    Wellington, Cheryl L / Yang, Yu-Zhou / Zhou, Stephen / Clee, Susanne M / Tan, Bing / Hirano, Kenichi / Zwarts, Karin / Kwok, Anita / Gelfer, Allison / Marcil, Michel / Newman, Scott / Roomp, Kirsten / Singaraja, Roshni / Collins, Jennifer / Zhang, Lin-Hua / Groen, Albert K / Hovingh, Kees / Brownlie, Alison / Tafuri, Sherrie /
    Genest, Jacques / Kastelein, John J P / Hayden, Michael R

    Journal of lipid research

    2002  Volume 43, Issue 11, Page(s) 1939–1949

    Abstract: Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower ... ...

    Abstract Mutations in ABCA1 uniformly decrease plasma HDL-cholesterol (HDL-C) and reduce cholesterol efflux, yet different mutations in ABCA1 result in different phenotypic effects in heterozygotes. For example, truncation mutations result in significantly lower HDL-C and apoliprotein A-I (apoA-I) levels in heterozygotes compared with nontruncation mutations, suggesting that truncation mutations may negatively affect the wild-type allele. To specifically test this hypothesis, we examined ABCA1 protein expression in response to 9-cis-retinoic acid (9-cis-RA) and 22-R-hydroxycholesterol (22-R-OH-Chol) in a collection of human fibroblasts representing eight different mutations and observed that truncation mutations blunted the response to oxysterol stimulation and dominantly suppressed induction of the remaining full-length allele to 5-10% of wild-type levels. mRNA levels between truncation and nontruncation mutations were comparable, suggesting that ABCA1 expression was suppressed at the protein level. Dominant negative activity of truncated ABCA1 was recapitulated in an in vitro model using transfected Cos-7 cells. Our results suggest that the severe reduction of HDL-C in patients with truncation mutations may be at least partly explained by dominant negative suppression of expression and activity of the remaining full-length ABCA1 allele. These data suggest that ABCA1 requires a physical association with itself or other molecules for normal function and has important pharmacogenetic implications for individuals with truncation mutations.
    MeSH term(s) ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters/biosynthesis ; ATP-Binding Cassette Transporters/chemistry ; ATP-Binding Cassette Transporters/genetics ; Alitretinoin ; Alleles ; Animals ; Apolipoprotein A-I/metabolism ; Fibroblasts ; Genes, Dominant ; Heterozygote ; Humans ; Hydroxycholesterols/pharmacology ; Lipoproteins, HDL/analysis ; Macrophages ; Mice ; Mutation/genetics ; Tretinoin/pharmacology ; Up-Regulation/drug effects
    Chemical Substances ABCA1 protein, human ; ATP Binding Cassette Transporter 1 ; ATP-Binding Cassette Transporters ; Apolipoprotein A-I ; Hydroxycholesterols ; Lipoproteins, HDL ; 22-hydroxycholesterol (17711-16-9) ; Alitretinoin (1UA8E65KDZ) ; Tretinoin (5688UTC01R)
    Language English
    Publishing date 2002-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80154-9
    ISSN 1539-7262 ; 0022-2275
    ISSN (online) 1539-7262
    ISSN 0022-2275
    DOI 10.1194/jlr.m200277-jlr200
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    Zs.A 175: Show issues Location:
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