본문 바로가기
KERD
논문KCI 등재

Revisiting PPARγ as a target for the treatment of metabolic disorders

박지영|최장현|최선실
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2014.11|BMB Reports|제47권 제11호|pp. 599-608

2

조회

0

다운로드

4

인용

0

참고문헌

키워드

PPARγMetabolic disordersInsulin sensitivityPost translational modification (PTMs)Thiazolidinediones (TZDs)
주제분류화학

초록

As the prevalence of obesity has increased explosively overthe last several decades, associated metabolic disorders,including type 2 diabetes, dyslipidemia, hypertension, andcardiovascular diseases, have been also increased. Thus, newstrategies for preventing and treating them are needed. Thenuclear peroxisome proliferator-activated receptors (PPARs)are involved fundamentally in regulating energy homeostasis;thus, they have been considered attractive drug targets foraddressing metabolic disorders. Among the PPARs, PPARγ is amaster regulator of gene expression for metabolism,inflammation, and other pathways in many cell types,especially adipocytes. It is a physiological receptor of thepotent anti-diabetic drugs of the thiazolidinediones (TZDs)class, including rosiglitazone (Avandia). However, TZDs haveundesirable and severe side effects, such as weight gain, fluidretention, and cardiovascular dysfunction. Recently, manyreports have suggested that PPARγ could be modulated bypost-translational modifications (PTMs), and modulation ofPTM has been considered as novel approaches for treatingmetabolic disorders with fewer side effects than the TZDs. Inthis review, we discuss how PTM of PPARγ may be regulatedand issues to be considered in making novel anti-diabeticdrugs that can modulate the PTM of PPARγ.

Abstract

As the prevalence of obesity has increased explosively overthe last several decades, associated metabolic disorders,including type 2 diabetes, dyslipidemia, hypertension, andcardiovascular diseases, have been also increased. Thus, newstrategies for preventing and treating them are needed. Thenuclear peroxisome proliferator-activated receptors (PPARs)are involved fundamentally in regulating energy homeostasis;thus, they have been considered attractive drug targets foraddressing metabolic disorders. Among the PPARs, PPARγ is amaster regulator of gene expression for metabolism,inflammation, and other pathways in many cell types,especially adipocytes. It is a physiological receptor of thepotent anti-diabetic drugs of the thiazolidinediones (TZDs)class, including rosiglitazone (Avandia). However, TZDs haveundesirable and severe side effects, such as weight gain, fluidretention, and cardiovascular dysfunction. Recently, manyreports have suggested that PPARγ could be modulated bypost-translational modifications (PTMs), and modulation ofPTM has been considered as novel approaches for treatingmetabolic disorders with fewer side effects than the TZDs. Inthis review, we discuss how PTM of PPARγ may be regulatedand issues to be considered in making novel anti-diabeticdrugs that can modulate the PTM of PPARγ.

참고문헌 (99)

  1. Chawla, A., "Nuclear receptors and lipid physiology: opening the X-files", Science, 5548, pp.1688~1670 (2001)
  2. Issemann, I., "Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators", Nature, 347, pp.645~650 (1990)
  3. Dreyer, C., "Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors", Cell, 68, pp.879~887 (1992)
  4. Evan, R. M., "PPARs and the complex journey to obesity", Nat. Med, 10, pp.355~361 (2004)
  5. Reddy, J. K., "Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system", Annu. Rev. Nutr, 21, pp.193~230 (2001)
  6. Peters, J. M., "Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta)", Mol. Cell. Biol, 20, pp.5119~5128 (2000)
  7. Oliver, W. R. Jr., "A selective peroxisome proliferator-activated receptors-delta agonist promotes reverse cholesterol transport", Proc. Natl. Acad. Sci. U.S.A, 98, pp.5306~5311 (2001)
  8. Risérus, U., "Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men", Diabetes, 57, pp.332~339 (2008)
  9. Tanaka, T., "Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome", Proc. Natl. Acad. Sci. U.S.A, 1000, pp.15924~15929 (2003)
  10. Lehmann, J. M, "An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)", J. Biol. Chem, 270, pp.12953~12956 (1995)
  11. Tontonoz, P., "Fat and beyond: the diverse biology of PPARgamma", Annu. Rev. Biochem, 77, pp.289~312 (2008)
  12. Tontonoz, P., "Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor", Cell, 79, pp.1147~1156 (1994)
  13. Barroso, I., "Dominant negative mutations in human PPARgamma associated with severe insulin resistance, diabetes mellitus and hypertension", Nature, 402, pp.880~883 (1999)
  14. Berger, J., "A PPARgamma mutant serves as a dominant negative inhibitor of PPAR signaling and is localized in the nucleus", Mol. Cell. Endocrinol, 162, pp.57~67 (2000)
  15. Barak, Y., "PPAR gamma is required for placental, cardiac, and adipose tissue development", Mol. Cell, 4, pp.585~595 (1999)
  16. Rosen, E. D., "PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro", Mol. Cell, 4, pp.611~617 (1999)
  17. Kubota, N., "PPARgamma mediates high-fat diet- induced adipocyte hypertrophy and insulin resistance", Mol. Cell, 4, pp.597~609 (1999)
  18. Gray, S. L., "Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator- activated receptor gamma function (P465L PPARgamma) in mice", Diabetes, 55, pp.2669~2677 (2006)
  19. Tamori, Y., "Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes", Diabetes, 51, pp.2045~2055 (2002)
  20. Rangwala, S. M., "Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity", Dev. Cell, 5, pp.657~663 (2003)
  21. He, W., "Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle", Proc. Natl. Acad. Sci. U.S.A, 100, pp.15712~15717 (2003)
  22. Hevener, A. L., "Muscle-specific PPARg deletion causes insulin resistance", Nat. Med, 9, pp.1491~1497 (2003)
  23. Matsusue, K., "Liverspecific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes", J. Clin. Invest, 111, pp.737~747 (2003)
  24. Norris, A. W., "Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones", J. Clin. Invest, 112, pp.608~618 (2003)
  25. Agarwal, A. K, "A novel heterozygous mutation in peroxisome proliferatoractivated receptor- gamma gene in a patient with familial partial lipodystrophy", J. Clin. Endocrinol. Metab, 87, pp.408~411 (2002)
  26. Hegele, R. A., "PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy", Diabetes, 51, pp.3586~3590 (2002)
  27. Savage, D. B, "Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor- gamma", Diabetes, 52, pp.910~917 (2003)
  28. Desvergne, B, "Peroxisome proliferator- activated receptors: nuclear control of metabolism", Endocr. Rev, 20, pp.649~688 (1999)
  29. Chandra, V., "Structure of the intact PPAR-gamma-RXR- nuclear receptor complex on DNA", Nature, 456, pp.350~356 (2008)
  30. Gronemeyer, H., "Principles for modulation of the nuclear receptor superfamily", Nat. Rev. Drug. Discov, 3, pp.950~964 (2004)
  31. Krey, G., "Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay", Mol. Endocrinol, 11, pp.779~791 (1997)
  32. Keller, H., "Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator- activated receptor-retinoid X receptor heterodimers", Proc. Natl. Acad. Sci. U.S.A, 90, pp.2160~2164 (1993)
  33. Forman, B. M., "15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma", Cell, 83, pp.803~812 (1995)
  34. Kliewer, S. A., "A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation", Cell, 83, pp.813~819 (1995)
  35. Nagy, L., "Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma", Cell, 93, pp.229~240 (1998)
  36. Kung, J., "Thiazolidinedione safety", Expert. Opin. Drug Saf, 11, pp.565~579 (2012)
  37. Nolan, J. J., "Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone", N. Engl. J. Med, 331, pp.1188~1193 (1994)
  38. Lehmann, J. M., "An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma)", J. Biol. Chem, 270, pp.12953~12956 (1995)
  39. Berger, J, "Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects", J. Biol. Chem, 274, pp.6718~6725 (1999)
  40. He, W., "Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle", Proc. Natl. Acad. Sci. U.S.A, 100, pp.15712~15717 (2003)
  41. Chao, L., "Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones", J. Clin. Invest, 106, pp.1221~1228 (2000)
  42. Matsusue, K., "Liverspecific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes", J. Clin. Invest, 111, pp.737~747 (2003)
  43. Ribon, V., "Thiazolidinediones and insulin resistance: peroxisome proliferator activated receptor g activation stimulates expression of the CAP gene", Proc. Natl. Acad. Sci. U.S.A, 95, pp.14751~14756 (1998)
  44. Rangwala, S. M., "Peroxisome proliferator- activated receptor gamma in diabetes and metabolism", Trends Pharmacol. Sci, 25, pp.331~336 (2004)
  45. Ye, J. M., "Direct demonstration of lipid sequestration as a mechanism by which rosiglitazone prevents fatty-acid-induced insulin resistance in the rat: comparison with metformin", Diabetologia, 47, pp.1306~1313 (2004)
  46. Burant, C. F., "Troglitazone action is independent of adipose tissue", J. Clin. Invest, 100, pp.2900~2908 (1997)
  47. Kim, J. K., "Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP", F-1 fatless mice, 2003, pp.52, 1311~1318
  48. Nan, Y. M., "Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice", Scand. J. Gastroenterol, 44, pp.358~365 (2009)
  49. Mayerson, A. B., "The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes", Diabetes, 51, pp.797~802 (2002)
  50. Musso, G., "Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials", Diabetologia, 55, pp.885~904 (2012)
  51. Kallwitz, E. R., "Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease", World J. Gastroenterol, 14, pp.22~28 (2008)
  52. Lutchman, G., "The effects of discontinuing pioglitazone in patients with nonalcoholic steatohepatitis", Hepatology, 46, pp.424~429 (2007)
  53. Gavrilova, O., "Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass", J. Biol. Chem, 278, pp.34268~34276 (2003)
  54. Lee, C. H., "Peroxisome proliferator- activated receptor-γ in macrophage lipid homeostasis", Trends Endocrinol. Metab, 13, pp.331~335 (2002)
  55. Hevener, A. L., "Macrophage PPARγ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones", J. Clin. Invest, 117, pp.1658~1669 (2007)
  56. Odegaard, J. I., "Macrophage-specific PPARγ controls alternative activation and improves insulin resistance", Nature, 447, pp.1116~1120 (2007)
  57. Yamauchi, T., "The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARγ agonist improve insulin resistance", J. Biol. Chem, 276, pp.41245~41254 (2001)
  58. Guan, H. P., "A futile metabolic cycle activated in adipocytes by antidiabetic agents", Nat. Med, 8, pp.1122~1128 (2002)
  59. Peraldi P., "Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling", J. Clin. Invest, 100, pp.1863~1869 (1997)
  60. Steppan, C. M., "The hormone resistin links obesity to diabetes", Nature, 409, pp.307~312 (2001)
  61. Rajala, M. W., "Adipose-derived resistin and gut-derived resistin- like molecule-gselectively impair insulin action on glucose production", J. Clin. Invest, 111, pp.225~300 (2003)
  62. Combs T. P., "Endogenous glucose production is inhibited by the adipose-derived protein Acrp30", J. Clin. Invest, 108, pp.1875~1881 (2001)
  63. Berg, A. H., "The adipocytesecreted protein Acrp30 enhances hepatic insulin action", Nat. Med, 7, pp.947~953 (2001)
  64. Yamauchi, T, "The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity", Nat. Med, 7, pp.941~946 (2001)
  65. Ahmadian, M., "PPARγ signaling and metabolism: the good, the bad and the future", Nat. Med, 19, pp.557~566 (2013)
  66. Miles, P. D., "Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency", J. Clin. Invest, 105, pp.287~292 (2000)
  67. Gregoire, F. M., "MBX-102", JNJ39659100, a novel peroxisome proliferator-activated receptor-ligand with weak transactivation activity retains antidiabetic properties in the absence of weight gain and edema, 2009, pp.23, 975~988
  68. selective modulator, "Mol. Endocrinol", 2003, 662~676
  69. Hu, E. D., "Inhibition of adipogenesis through MAP kinase mediated phosphorylation of PPAR gamma", Science, 274, pp.2100~2103 (1996)
  70. Tang, X., "An RNA interference-based screen identifies MAP4K4", NIK as a negative regulator of PPAR gamma, adipogenesis, and insulin-responsive hexose transport, 2006, pp.103, 2087~2092
  71. Camp, H. S., "Regulation of peroxisome proliferator-activated receptor gamma activity by mitogen-activated protein kinase", J. Biol. Chem, 272, pp.10811~10816 (1997)
  72. Reginato, M. J., "Prostaglandins promote and block adipogenesis through opposing effects on peroxisome proliferator- activated receptor gamma", J. Biol. Chem, 273, pp.1855~1858 (1998)
  73. Zhang, B., "Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator- activated receptor gamma", J. Biol. Chem, 271, pp.31771~31774 (1996)
  74. Adams, M., "Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen- activated protein kinase site", J. Biol. Chem, 272, pp.5128~5132 (1997)
  75. Shao, D., "Interdomain communication regulating ligand binding by PPAR-gamma", Nature, 396, pp.377~380 (1998)
  76. Rangwala, S. M., "Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity", Dev. Cell, 5, pp.657~663 (2003)
  77. Compe, E., "Dysregulation of the peroxisome proliferator-activated receptor target genes by XPD mutations", Mol. Cell. Biol, 25, pp.6065~6076 (2005)
  78. Iankova, I., "Peroxisome proliferator- activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis", Mol. Endocrinol, 20, pp.1494~1505 (2006)
  79. Choi, J. H., "Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5", Nature, 466, pp.451~456 (2010)
  80. Dhavan, R., "A decade of CDK5", Nat. Rev. Mol. Cell Biol, 2, pp.749~759 (2001)
  81. Li P, Fan W, Xu, J., "Adipocyte NCoR knockout decreases PPARγ phosphorylation and enhances PPARγ activity and insulin sensitivity", Cell, 147, pp.815~826 (2011)
  82. Geiss-Friedlander, R., "Concepts in sumoylation: a decade on", Nat. Rev. Mol. Cell Biol, 8, pp.947~956 (2007)
  83. Werman, A., "Ligand-independent activation domain in the N terminus of peroxisome proliferator- activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin", J. Biol. Chem, 272, pp.20230~20235 (1997)
  84. Hietakangas, V., "PDSM, a motif for phosphorylation-dependent SUMO modification", Proc. Natl. Acad. Sci. U.S.A, 103, pp.45~50 (2006)
  85. Yamashita, D., "The transactivating function of peroxisome proliferator-activated receptor gamma is negatively regulated by SUMO conjugation in the amino- terminal domain", Genes Cells, 9, pp.1017~1029 (2004)
  86. Dutchak, P. A., "Fibroblast growth factor-21 regulates PPARgamma activity and the antidiabetic actions of thiazolidinediones", Cell, 148, pp.556~567 (2012)
  87. Pascual, G., "A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma", Nature, 437, pp.759~763 (2005)
  88. Hauser, S., "Degradation of the peroxisome proliferatoractivated receptor gamma is linked to ligand-dependent activation", J. Biol. Chem, 275, pp.18527~18533 (2000)
  89. Floyd, Z. E., "Interferon-gammamediated activation and ubiquitin-proteasomedependent degradation of PPAR gamma in adipocytes", J. Biol. Chem, 277, pp.4062~4068 (2002)
  90. Kilroy, G. E., "PPAR-gamma AF-2 domain functions as a component of a ubiquitin- dependent degradation signal", Obesity (Silver Spring), 17, pp.665~673 (2009)
  91. Ji, S., "O-GlcNAc modification of PPARγ reduces its transcriptional activity", Biochem. Biophys. Res. Commun, 417, pp.1158~1163 (2012)
  92. Wang, C., "Acetylation and nuclear receptor action", J. Steroid Biochem. Mol. Biol, 123, pp.91~100 (2011)
  93. Li, A., "Prediction of Nepsilon-acetylation on internal lysines implemented in Bayesian Discriminant Method", Biochem. Biophys. Res. Commun, 350, pp.818~824 (2006)
  94. Qiang, L., "Brown remodeling of white adipose tissue by SirT1-dependent deacetylation of Pparγ", Cell, 150, pp.620~632 (2012)
  95. Acton, J. J. 3rd., "Benzoyl 2-methyl indoles as selective PPARgamma modulators", Bioorg. Med. Chem. Lett, 15, pp.357~362 (2005)
  96. Choi, J. H, "Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation", Nature, 477, pp.477~481 (2011)
  97. Harms, M., "Brown and beige fat: development, function and therapeutic potential", Nat. Med, 19, pp.1252~1263 (2013)
  98. Petrovic, N., "Chronic peroxisome proliferator-activated receptor γ (PPARγ) activation of epididymally derived white adipocyte cultures reveals a population of thermogenically competent, UCP1-containing adipocytes molecularly distinct from classic brown adipocytes", J. Biol. Chem, 285, pp.7153~7164 (2010)
  99. Ohno, H., "PPARγ agonists induce a white-to-brown fat conversion through stabilization of PRDM16 protein", Cell Metab, 15, pp.395~404 (2012)

관련 논문AI추천

PPARγ Agonist Beyond Glucose Lowering Effect양철우, Akira Sugawara, Akira Uruno, Ken Matsuda, Masataka Kudo, Sadayoshi Ito대한내과학회 · The Korean Journal of Internal Medicine2011 · 제26권 제1호The Regulatory Effects of Trans-chalcone on Adipogenesis한연호대한구강생물학회 · International Journal of Oral Biology2018 · 제43권 제1호제 2형 당뇨병 치료제의 개발 동향김익환, 이수현, 이종근한국미생물·생명공학회 · 한국미생물·생명공학회지2012 · 제40권 제3호Ret finger protein deficiency attenuates adipogenesis in male mice with high fat diet-induced obesityCho Hye Jung, Eom Gwang Hyeon, Jeong Anna, Joung Hosouk, Kim Hyung Seok, Kook Hyun, Kwon Duk-Hwa, Lee Su-Jin, Lee Yun-Gyeong, Lim Yongwoon, Nam Kwang-Il, Park Byung-Hyun, Park So-Young, Shin Sera, Yu Hwang Chan생화학분자생물학회 · Experimental and Molecular Medicine2025 · 제57권 The role of lipids in the pathogenesis and treatment of type 2 diabetes and associated co-morbidities박현준, 이희영, Derek M. Erion생화학분자생물학회 · BMB Reports2016 · 제49권 제3호Bile Acid Receptor Farnesoid X Receptor: A Novel Therapeutic Target for Metabolic Diseases황성순한국지질동맥경화학회 · 지질·동맥경화학회지2017 · 제6권 제1호

이 간행물의 다른 논문 (7건)

Enzymatic DNA oxidation: mechanisms and biological significanceColum P. Walsh, Guo-Liang Xupp. 609-618Effects of different target sites on antisense RNA-mediated regulation of gene expression이지영, 석신애, 윤영성, 박홍만, 이영훈pp. 619-624Structure-activity relationships of the intramolecular disulfide bonds in coprisin, a defensin from the dung beetle김호, 이동건, 이다은, 최혜민, 김재일, 김하형, 황재삼, 이재호pp. 625-630Aurora-A kinase-inactive mutants disrupt the interaction with Ajuba and cause defects in mitotic spindle formation and G2/M phase arrest in HeLa cellsQiang Huang, Meirong Bai, Yichen Le, Long Yu, Jun Ni, Suqin Shen, Jiaxue Wupp. 631-636Sulodexide inhibits retinal neovascularization in a mouse model of oxygen-induced retinopathy조형, 정상훈, 임혜빈, 강준, 강규동pp. 637-642
원문 보기