Therapeutic Role of Peroxisome Proliferator-Activated Receptors Gamma in the Treatment of Fibrosis
DOI:
https://doi.org/10.7439/ijbr.v7i6.3390Keywords:
Physical activity, IPAQ, MET score, WHR.Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that regulate many physiological processes. Recent studies have implicated PPARs in the control of fibrosis. In particular, agonists of PPARg have been found to have antifibrotic effects on a number of tissues including the lung, heart, and liver. This antifibrotic effect is related to the inhibition of TGF-?/ Smad signal transduction including other pathways that still remain unidentified. This review focuses on PPARg and its mode of activation in relation to fibrosis.Downloads
References
Dreyer, C., et al., Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell, 1992. 68(5): p. 879-87.
Schmidt, A., et al., Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol, 1992. 6(10): p. 1634-41.
Kliewer, S.A., et al., Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A, 1994. 91(15): p. 7355-9.
Mangelsdorf, D.J., et al., The nuclear receptor superfamily: the second decade. Cell, 1995. 83(6): p. 835-9.
Mukherjee, R., et al., Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol, 1994. 51(3-4): p. 157-66.
Braissant, O., et al., Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat. Endocrinology, 1996. 137(1): p. 354-66.
Auboeuf, D., et al., Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients. Diabetes, 1997. 46(8): p. 1319-27.
Brown, J.D. and J. Plutzky, Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation, 2007. 115(4): p. 518-33.
Evans, R.M., G.D. Barish, and Y.X. Wang, PPARs and the complex journey to obesity. Nat Med, 2004. 10(4): p. 355-61.
Tontonoz, P., et al., mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev, 1994. 8(10): p. 1224-34.
Zhu, Y., et al., Structural organization of mouse peroxisome proliferator-activated receptor gamma (mPPAR gamma) gene: alternative promoter use and different splicing yield two mPPAR gamma isoforms. Proc Natl Acad Sci U S A, 1995. 92(17): p. 7921-5.
Chawla, A., et al., Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology, 1994. 135(2): p. 798-800.
Keller, J.M., et al., Implications of peroxisome proliferator-activated receptors (PPARS) in development, cell life status and disease. Int J Dev Biol, 2000. 44(5): p. 429-42.
Chawla, A., et al., PPARdelta is a very low-density lipoprotein sensor in macrophages. Proc Natl Acad Sci U S A, 2003. 100(3): p. 1268-73.
Ziouzenkova, O., et al., Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase. Proc Natl Acad Sci U S A, 2003. 100(5): p. 2730-5.
Ahmed, W., et al., High-density lipoprotein hydrolysis by endothelial lipase activates PPARalpha: a candidate mechanism for high-density lipoprotein-mediated repression of leukocyte adhesion. Circ Res, 2006. 98(4): p. 490-8.
Tontonoz, P., E. Hu, and B.M. Spiegelman, Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell, 1994. 79(7): p. 1147-56.
Chawla, A., et al., Nuclear receptors and lipid physiology: opening the X-files. Science, 2001. 294(5548): p. 1866-70.
Rosen, E.D. and B.M. Spiegelman, PPARgamma : a nuclear regulator of metabolism, differentiation, and cell growth. J Biol Chem, 2001. 276(41): p. 37731-4.
Knouff, C. and J. Auwerx, Peroxisome proliferator-activated receptor-gamma calls for activation in moderation: lessons from genetics and pharmacology. Endocr Rev, 2004. 25(6): p. 899-918.
Lehrke, M. and M.A. Lazar, The many faces of PPARgamma. Cell, 2005. 123(6): p. 993-9.
Werman, A., et al., 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, 1997. 272(32): p. 20230-5.
Heikkinen, S., J. Auwerx, and C.A. Argmann, PPARgamma in human and mouse physiology. Biochim Biophys Acta, 2007. 1771(8): p. 999-1013.
Issemann, I., et al., The peroxisome proliferator-activated receptor:retinoid X receptor heterodimer is activated by fatty acids and fibrate hypolipidaemic drugs. J Mol Endocrinol, 1993. 11(1): p. 37-47.
Keller, H., et al., 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, 1993. 90(6): p. 2160-4.
Nakshatri, H. and P. Bhat-Nakshatri, Multiple parameters determine the specificity of transcriptional response by nuclear receptors HNF-4, ARP-1, PPAR, RAR and RXR through common response elements. Nucleic Acids Res, 1998. 26(10): p. 2491-9.
Hertz, R., et al., Fatty acyl-CoA thioesters are ligands of hepatic nuclear factor-4alpha. Nature, 1998. 392(6675): p. 512-6.
Tontonoz, P. and B.M. Spiegelman, Fat and beyond: the diverse biology of PPARgamma. Annu Rev Biochem, 2008. 77: p. 289-312.
Michalik, L., et al., International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev, 2006. 58(4): p. 726-41.
Brown, J.D. and J. Plutzky, Peroxisome Proliferator Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets. Circulation, 2007. 115(4): p. 518-533.
Everett, L., A. Galli, and D. Crabb, The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease. Liver, 2000. 20(3): p. 191-9.
Guan, H.P., et al., Corepressors selectively control the transcriptional activity of PPARgamma in adipocytes. Genes Dev, 2005. 19(4): p. 453-61.
Herzig, S., et al., CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature, 2001. 413(6852): p. 179-83.
Puigserver, P. and B.M. Spiegelman, Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator. Endocr Rev, 2003. 24(1): p. 78-90.
Handschin, C. and B.M. Spiegelman, Peroxisome proliferator-activated receptor gamma coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr Rev, 2006. 27(7): p. 728-35.
Lakatos, H.F., et al., The Role of PPARs in Lung Fibrosis. PPAR Res, 2007. 2007: p. 71323.
Milam, J.E., et al., PPAR-gamma agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2008. 294(5): p. L891-901.
Yang, L., et al., Regulation of peroxisome proliferator-activated receptor-gamma in liver fibrosis. Am J Physiol Gastrointest Liver Physiol, 2006. 291(5): p. G902-11.
Wang, W., F. Liu, and N. Chen, Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists attenuate the profibrotic response induced by TGF-beta1 in renal interstitial fibroblasts. Mediators Inflamm, 2007. 2007: p. 62641.
Duhaney, T.A., et al., Peroxisome proliferator-activated receptor alpha-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload. Hypertension, 2007. 49(5): p. 1084-94.
Friedman, S.L., Liver fibrosis -- from bench to bedside. J Hepatol, 2003. 38 Suppl 1: p. S38-53.
Marra, F., Hepatic stellate cells and the regulation of liver inflammation. J Hepatol, 1999. 31(6): p. 1120-30.
Milani, S., et al., Procollagen expression by nonparenchymal rat liver cells in experimental biliary fibrosis. Gastroenterology, 1990. 98(1): p. 175-84.
Bataller, R. and D.A. Brenner, Liver fibrosis. J Clin Invest, 2005. 115(2): p. 209-18.
Arthur, M.J., Fibrogenesis II. Metalloproteinases and their inhibitors in liver fibrosis. Am J Physiol Gastrointest Liver Physiol, 2000. 279(2): p. G245-9.
Wang, Z., et al., Peroxisome proliferator-activated receptor gamma inhibits hepatic fibrosis in rats. Hepatobiliary Pancreat Dis Int. 10(1): p. 64-71.
Bennett, R.G., K.K. Kharbanda, and D.J. Tuma, Inhibition of markers of hepatic stellate cell activation by the hormone relaxin. Biochem Pharmacol, 2003. 66(5): p. 867-74.
Singh, S. and R.G. Bennett, Relaxin signaling activates peroxisome proliferator-activated receptor gamma. Mol Cell Endocrinol, 2010. 315(1-2): p. 239-45.
Miyahara, T., et al., Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem, 2000. 275(46): p. 35715-22.
Singh, S. and R.G. Bennett, Dominant-negative and knockdown approaches to studying PPAR activity. Methods Mol Biol, 2013. 952: p. 87-98.
Singh, S. and R.G. Bennett, Relaxin family peptide receptor 1 activation stimulates peroxisome proliferator-activated receptor gamma. Ann N Y Acad Sci, 2009. 1160: p. 112-6.
Singh, S. and R.G. Bennett, Relaxin activation of PPAR [gamma] is ligand independent. The FASEB Journal, 2009. 23(1 Supplement): p. 706.3-706.3.
Singh, S., R.L. Simpson, and R.G. Bennett, Relaxin activates peroxisome proliferator-activated receptor gamma (PPARgamma) through a pathway involving PPARgamma coactivator 1alpha (PGC1alpha). J Biol Chem, 2015. 290(2): p. 950-9.
Bennett, R.G., et al., Relaxin decreases the severity of established hepatic fibrosis in mice. Liver International, 2014. 34(3): p. 416-426.
Leclercq, I.A., et al., Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats. Gut, 2006. 55(7): p. 1020-9.
Wallace, K., A.D. Burt, and M.C. Wright, Liver fibrosis. Biochem J, 2008. 411(1): p. 1-18.
Mazella, J., M. Tang, and L. Tseng, Disparate effects of relaxin and TGFbeta1: relaxin increases, but TGFbeta1 inhibits, the relaxin receptor and the production of IGFBP-1 in human endometrial stromal/decidual cells. Hum Reprod, 2004. 19(7): p. 1513-8.
Samuel, C.S., et al., Relaxin deficiency in mice is associated with an age-related progression of pulmonary fibrosis. Faseb J, 2003. 17(1): p. 121-3.
Fan, Z. and J. Guan, Antifibrotic therapies to control cardiac fibrosis. Biomater Res, 2016. 20: p. 13.
Dantas, A.T., et al., The Role of PPAR Gamma in Systemic Sclerosis. PPAR Res, 2015. 2015: p. 124624.
Liu, H.J., et al., Peroxisome Proliferator-Activated Receptor-gamma Is Critical to Cardiac Fibrosis. PPAR Res, 2016. 2016: p. 2198645.
Downloads
Published
Issue
Section
License
Authors who publish with this journal agree to the following terms:
- Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgment of the work's authorship and initial publication in this journal.
- Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgment of its initial publication in this journal.
- Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).
- An author must submit Copyright form After acceptance of the article.