PPAR Research

PPAR Research / 2009 / Article
Special Issue

PPARs in Viral Disease

View this Special Issue

Review Article | Open Access

Volume 2009 |Article ID 357204 | https://doi.org/10.1155/2009/357204

Sébastien Dharancy, Maud Lemoine, Philippe Mathurin, Lawrence Serfaty, Laurent Dubuquoy, "Peroxisome Proliferator-Activated Receptors in HCV-Related Infection", PPAR Research, vol. 2009, Article ID 357204, 5 pages, 2009. https://doi.org/10.1155/2009/357204

Peroxisome Proliferator-Activated Receptors in HCV-Related Infection

Academic Editor: Jacqueline Capeau
Received18 Oct 2008
Accepted06 Jan 2009
Published30 Mar 2009


The topic of peroxisome proliferator-activated receptors has been developed in the field of hepatology allowing envisaging therapeutic strategies for the most frequent chronic liver diseases such as chronic infection with hepatitis C virus (HCV). PPARs contribute to wide physiological processes within the liver such as lipid/glucid metabolisms, inflammatory response, cell differentiation, and cell cycle. In vitro experiments and animal studies showed that PPAR discloses anti-inflammatory property, and PPAR discloses anti-inflammatory, antifibrogenic, and antiproliferative properties in the liver. Experimental and human studies showed impaired PPARs expression and function during HCV infection. The available nonhepatotoxic agonists of PPARs may constitute a progress in the therapeutic management of patients chronically infected with HCV.

1. Introduction

Chronic infection with the hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide, affecting about 3% of the population [1]. The natural history of HCV infection is characterized by a high rate of progression to chronic hepatitis leading, in at least 20% of cases, to cirrhosis and ultimately to hepatocellular carcinoma [2, 3]. The precise mechanisms underlying HCV-related liver injury are not well understood but involve a cell-mediated immune response with lymphocytic infiltration leading to a chronic inflammatory response and progressive scale fibrosis which are dependent on proinflammatory and fibrogenic mediators. HCV infection is also characterized by disruption of lipid and glucid metabolisms leading to hepatocyte fat accumulation (also called hepatic steatosis) and an increase risk of diabetes [47]. These latter are under dependence, at least in part, of peroxisome proliferator-activated receptors functions.

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily and require heterodimerization with receptor X for retinoids (RXR) in order to function [8]. The first PPAR identified was murine PPAR [9]. Since its description in 1990, a family of homologous receptors has been identified in various species. The PPAR family includes three subtypes: PPAR (NR1C1), PPAR (PPAR or NR1C2), and PPAR (NR1C3) [10]. PPAR / , together with their obligate partner RXR, are the three main nuclear receptors expressed in the liver. These receptors contribute to the great diversity of physiological processes in the liver, such as control of lipid and glucid metabolisms, inflammatory responses, and cellular differentiation and proliferation. PPAR activation has been associated with anti-inflammatory and antifibrotic functions in the liver. In light of their multiple activities, PPARs quickly became considered as therapeutic targets of the most widespread human metabolic diseases (obesity, diabetes, and atherosclerosis). The development of new nonhepatotoxic ligands made it possible to use PPARs as new therapeutic targets in hepatology. For these reasons, recent discoveries in the field of PPARs are of intense interest not only to fundamental researchers but to clinicians as well. This review will first describe the main functions of PPARs within the liver. Then the interactions between PPARs and HCV will be developed to provide a precise picture of the potential role of PPARs in HCV pathophysiology and therapy.

2. Control of Lipid and Lipoprotein Metabolism

PPAR is strongly involved in the control of lipid and lipoprotein metabolisms. PPAR mice display minimal accumulation of triglycerides in the liver under fed conditions, but manifest an exaggerated steatotic response to fasting [11]. Moreover, PPAR mice fed a high-fat diet showed massive accumulation of lipids in the liver, highlighting its crucial role in lipid metabolism [12]. Intracellular fatty acid (FA) concentrations are controlled, in part, by regulation of the FA import and export system. PPARs control the uptake of FA in liver; for example, PPAR agonists control expression of the FA transport protein (FATP-1) responsible for FA transport across the cell membrane, FA translocase (FAT/CD36), and the hepatic cytosolic FA binding protein (L-FABP) involved in FA trafficking [13]. The absence of induction of FATP-1 and FAT/CD36 mRNA in liver by PPAR activators has been well demonstrated in PPAR mice. PPAR and - also prevent the efflux of FA by promoting their activation into fatty acyl CoA thioesters by the acyl-CoA synthetase ACS [14, 15]. In addition, PPAR stimulates activated FA catabolism by the peroxisomal, microsomal, and mitochondrial -oxidation systems. It regulates the expression of genes coding for enzymes such as acyl-CoA oxidase (AOX), the first and main enzyme in the classic peroxisomal -oxidation system. It also activates the transcription of genes encoding for classical microsomal -oxidation system cytochrome P450 CYP4A (A1 and A3) isoforms, and stimulates activated FA catabolism by mitochondrial -oxidation. It is generally accepted that oxidation of long-chain FA is regulated at the level of the liver carnitine palmitoyl-transferase I (LCPT1), whose product catalyzes the initial step in long-chain FA import into mitochondria. PPAR has been demonstrated to affect FA import into mitochondria by upregulating expression of the LCPT1 gene [14]. Concerning PPAR , treatment of HepG2 with troglitazone, a synthetic agonist, specifically increased recycling by peroxisomal -oxidation of C18 to C16 FAs, and the interconversion of long-chain FAs was associated with reduced de novo lipogenesis. It is conceivable that these effects of troglitazone on oxidation, interconversion, and synthesis-saturated FA play a major role in cellular energy metabolism, membrane lipid composition and turnover [16].

It has been convincingly established that PPAR activation increases plasma HDL cholesterol and enhances reverse cholesterol transport via the induction of hepatic apolipoprotein A-I and apolipoprotein A-II expression in human liver. Nevertheless, PPAR activators affect HDL metabolism in an opposite manner in rodents and humans. While fibrate treatment of rats lowers plasma HDL, an increase is generally observed in humans; such an increase in HDL plasma levels is related, at least in part, to changes in apoAI and apoA-II gene expression in liver. ApoA-I and apoA-II gene transcription is upregulated in humans and repressed in rodents by PPAR activators. Treatment of human primary hepatocytes with fibrates increases mRNA levels and secretion of apoA-I. Moreover, in patients with familial combined hyperlipoproteinemia, ciprofibrate administration enhances production of apoA-I [17].

3. Anti-Inflammatory and Immunomodulatory Properties of PPAR in the Liver

PPAR exert catabolic function through peroxisomal, microsomal, and mitochondrial -oxydation pathways, and therefore allows the use of FA by hepatocytes as energetic substrate. Thus, it degrades several lipid inflammatory mediators (prostaglandins, leukotriens) using these metabolic pathways [18, 19]. There are numerous experimental and clinical evidences in favor of anti-inflammatory activity of PPAR in the liver. PPAR and PPAR were shown to negatively interfere with the nuclear factor (NF)- B, signal transducers and activators of transcription (STAT), and activating protein 1 (AP-1) signalling pathways in primary hepatocyte cultures and monocytes/macrophages [20, 21]. Delerive et al. showed that fibrates, which are the main synthetic agonists of PPAR induced the expression of I B protein in primary human hepatocytes, whereas neither I B kinase activity nor the degradation rate of I B was affected. The consequence is that the downstream inflammatory responses genes such as IL-2, IL-6, IL-8, TNF , and metalloproteases are inhibited [20]. PPAR can also control hepatic inflammation by regulating hemostatic factors and acute-phase response proteins in hepatocytes [22].

T-lymphocytes, natural killer cells, and monocytes/macrophages express significant amount of PPAR and when activated, and they inhibit the production of inflammatory and immunomodulatory activity cytokines [2328]. In lymphocytes, immunomodulatory activity is supported by a decrease in nuclear factor of activated T-cells (NFAT) activity which regulate IL-2 promoter [23, 29]. PPAR inhibit the proliferation of T-lymphocytes and the production of IFN , TNF , and IL-2 [30].

Animal studies confirmed the role of PPAR and PPAR in inflammation control showing that PPAR mice display a prolonged response to inflammation induced by arachidonic acid or zymosan [3133]. Interestingly, PPAR and PPAR mice displayed an exacerbated sensibility to hepatitis in different models of liver injury [34, 35].

4. Antifibrogenic Activities of PPAR in the Liver

Hepatic stellate cells (HSCs) are the main cells responsible for liver modulation, by producing the protein of the extracellular matrix [36, 37]. In response to liver injury, HSC changes from a quiescent to an activated phenotype. This activation process includes a phenotypic change to a myofibroblast-like cell, an increased proliferation rate, loss of retinoid stores, and increased production of extracellular matrix proteins, chemokines, cytokines, and contractility. Interestingly, HSC activation is associated with impaired expression of PPAR and with a decrease in binding to the peroxisome proliferator response element (PPRE) in vivo, whereas NF B and AP-1 binding is increased. HSC activation is reversed by treatment with PPAR agonists in vitro, suggesting antifibrogenic activity [38, 39]. PPAR activation dose-dependently inhibited HSC proliferation and chemotaxis induced by platelet-derived growth factor. This effect was independent of changes in postreceptor signalling or expression of c-fos and c-myc, and was associated with inhibition of cell progression beyond the G1 phase. PPAR activation also resulted in complete inhibition of the expression of monocyte chemotactic protein (MCP1), a potent chemoattractant for monocytes and T-lymphocytes [40]. All things considered, PPAR activation in vitro resulted in decreases in HSC proliferation, migration, and chemokine expression, three pivotal actions relevant to the process of liver wound healing and fibrogenesis. A study performed in a model of liver fibrosis induced by dimethylnitrosamine or carbon tetrachloride showed that oral administration of pioglitazone or rosiglitazone reduces hepatic extracellular matrix deposition and HSC activation [41]. PPAR ligands may also have rescue effects on hepatic fibrosis. Using thioacetamide models of liver cirrhosis, animals treated with a diet containing one of the two PPAR ligands, Wy-14 643 (WY) or fenofibrate, displayed reduced hepatic fibrosis. PPAR ligands had an antifibrotic action in the thioacetamine model of liver cirrhosis, probably due to an antioxidant effect of enhanced catalase expression and activity in the liver [42].

5. Interaction between HCV and PPARs

Liver inflammation, hepatocyte fat accumulation, and diabetes are three pivotal hallmarks in the natural history of chronic HCV infection which are at least in part controlled by PPARs. Thus, it was tempting for several teams to investigate whether PPAR / may be impaired and/or nonfunctional, and might therefore play a role in the physiopathology of HCV infection.

Numerous studies have demonstrated that PPAR / were physiologically highly expressed by parenchymal hepatic cells, where they play a pivotal anti-inflammatory and metabolic role. Several teams have demonstrated, using in vitroand ex vivo approaches, a decrease expression and functional activity of PPAR in hepatocytes during HCV infection, which may contribute to the pathogenesis of the disease. (1) During chronic HCV infection in humans [43, 44], (2) in an experimental model of transgenic mouse [4], and (3) in transfected hepatocytes expressing the capsid protein of HCV [4, 43, 44]. These abnormalities may be the consequence of viral capsid inhibiting transcriptional activity of genes involved in lipid metabolism of infected host cell [4, 43, 44].

In the same line, De Gottardi et al. showed that (1) PPAR expression was significantly lower in genotype 3 compared with genotype 1 HCV infection and (2) steatosis was associated to decreased levels of PPAR in genotype 1 HCV infection. In this study, there was no significant relationship between PPARs mRNA levels and liver activity or fibrosis. The presences of steatosis and hepatitis C virus genotype 3 were both associated with a significant downregulation of PPARs [44].

The ways in which impaired expression of PPAR / contribute to the pathogenesis of HCV hepatitis are numerous. As previously described, PPAR activators play a regulatory role in the inflammatory response at the hepatic level by inhibiting cytokines and acute-phase inflammatory protein production by negatively interfering with NF- B and AP-1 pathways. Clinical evidence for the anti-inflammatory role of PPAR in the liver was provided by the characterization of PPAR mice which were more susceptible to various hepatotoxic compounds and had delayed liver regeneration compared to their wild-type littermates. A recent study also demonstrated that activation of PPAR limits the expression of the TH1 cytokine profile and TNF production by human CD4-positive T-cells, a cytokine pattern known to substantially contribute to HCV pathogenesis.

Preliminary human data reinforce interest in this topic. Two pilot studies suggested therapeutic effects of bezafibrate, an agonist of PPAR / / , during chronic HCV infection. In the first open trial, 30 patients unresponsive to interferon monotherapy were treated for 6 months with 400 mg/day [45]. At endpoint, viral load and liver enzymes were significantly decreased, suggesting anti-inflammatory and antiviral activities of bezafibrate. More recently, 7 patients received 400 mg/day of bezafibrate for 8 weeks. Once again, ALT, AST, and viral load were lowered compared to baseline [46]. Taken together, these results may argue in favor of restoration of transcriptional activity of the hepatoprotective PPAR and/or PPAR receptors during chronic HCV infection. Pioglitazone, an agonist of PPAR , is currently evaluated in patient with chronic HCV infection and insulin resistance (http://clinicaltrials.gov/show/NCT00189163).

6. Conclusion

Chronic infection with HCV is a major cause of chronic liver disease worldwide and is associated with chronic liver inflammation, hepatocyte fat accumulation, and diabetes. Nuclear hormone receptors PPAR and are involved in the transduction of metabolic and nutritional signals into transcriptional responses in order to maintain liver homeostasis. Evidence exists in favor of a decreased expression and functional activity of PPAR / in hepatocytes during HCV infection related to HCV core protein, suggesting that HCV may have evolved strategies to prevent inducing, or to overcome, an efficient response by the host. This decreased expression of PPAR / may be involved in the pathogenesis of HCV infection through an alteration of the protective effects of these nuclear receptors against hepatic inflammation and fibrosis. Taken together, all these considerations suggest that PPAR / may represent new potential therapeutic targets in HCV infection.

PPAR:Peroxisome proliferator-activated receptor
RXR:Retinoid X receptor
HCV:Hepatitis C virus
FA:Fatty acid.


  1. World Health Organization, “Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium,” Journal of Viral Hepatitis, vol. 6, no. 1, pp. 35–47, 1999. View at: Publisher Site | Google Scholar
  2. H. B. El-Serag, “Hepatocellular carcinoma and hepatitis C in the United States,” Hepatology, vol. 36, pp. S74–S83, 2002. View at: Publisher Site | Google Scholar
  3. L. B. Seeff, “Natural history of chronic hepatitis C,” Hepatology, vol. 36, pp. S35–S46, 2002. View at: Publisher Site | Google Scholar
  4. A. Yamaguchi, S. Tazuma, T. Nishioka et al., “Hepatitis C virus core protein modulates fatty acid metabolism and thereby causes lipid accumulation in the liver,” Digestive Diseases and Sciences, vol. 50, no. 7, pp. 1361–1371, 2005. View at: Publisher Site | Google Scholar
  5. L. Serfaty, T. Andreani, P. Giral, N. Carbonell, O. Chazouillères, and R. Poupon, “Hepatitis C virus induced hypobetalipoproteinemia: a possible mechanism for steatosis in chronic hepatitis C,” Journal of Hepatology, vol. 34, no. 3, pp. 428–434, 2001. View at: Publisher Site | Google Scholar
  6. V. Ratziu, A. Heurtier, L. Bonyhay, T. Poynard, and P. Giral, “Review article: an unexpected virus-host interaction—the hepatitis C virus-diabetes link,” Alimentary Pharmacology & Therapeutics, vol. 22, pp. 56–60, 2005. View at: Publisher Site | Google Scholar
  7. C. O. Zein, C. Levy, A. Basu, and N. N. Zein, “Chronic hepatitis C and type II diabetes mellitus: a prospective cross-sectional study,” The American Journal of Gastroenterology, vol. 100, no. 1, pp. 48–55, 2005. View at: Publisher Site | Google Scholar
  8. S. A. Kliewer, K. Umesono, D. J. Noonan, R. A. Heyman, and R. M. Evans, “Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors,” Nature, vol. 358, no. 6389, pp. 771–774, 1992. View at: Publisher Site | Google Scholar
  9. I. Issemann and S. Green, “Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators,” Nature, vol. 347, no. 6294, pp. 645–650, 1990. View at: Publisher Site | Google Scholar
  10. Nuclear Receptors Nomenclature Committee, “A unified nomenclature system for the nuclear receptor superfamily,” Cell, vol. 97, no. 2, pp. 161–163, 1999. View at: Publisher Site | Google Scholar
  11. M. S. Rao and J. K. Reddy, “Peroxisomal β-oxidation and steatohepatitis,” Seminars in Liver Disease, vol. 21, no. 1, pp. 43–55, 2001. View at: Publisher Site | Google Scholar
  12. P. Gervois, I. P. Torra, J.-C. Fruchart, and B. Staels, “Regulation of lipid and lipoprotein metabolism by PPAR activators,” Clinical Chemistry and Laboratory Medicine, vol. 38, no. 1, pp. 3–11, 2000. View at: Publisher Site | Google Scholar
  13. P. Escher and W. Wahli, “Peroxisome proliferator-activated receptors: insight into multiple cellular functions,” Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, vol. 448, no. 2, pp. 121–138, 2000. View at: Publisher Site | Google Scholar
  14. M.-H. Hsu, Ü. Savas, K. J. Griffin, and E. F. Johnson, “Identification of peroxisome proliferator-responsive human genes by elevated expression of the peroxisome proliferator-activated receptor α in HepG2 cells,” The Journal of Biological Chemistry, vol. 276, no. 30, pp. 27950–27958, 2001. View at: Publisher Site | Google Scholar
  15. G. Martin, K. Schoonjans, A.-M. Lefebvre, B. Staels, and J. Auwerx, “Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARα and PPARγ activators,” The Journal of Biological Chemistry, vol. 272, no. 45, pp. 28210–28217, 1997. View at: Publisher Site | Google Scholar
  16. W.-N. P. Lee, S. Lim, S. Bassilian, E. A. Bergner, and J. Edmond, “Fatty acid cycling in human hepatoma cells and the effects of troglitazone,” The Journal of Biological Chemistry, vol. 273, no. 33, pp. 20929–20934, 1998. View at: Publisher Site | Google Scholar
  17. J. Turay, V. Grniaková, and J. Valka, “Changes in paraoxonase and apolipoprotein A-I, B, C-III and E in subjects with combined familiar hyperlipoproteinemia treated with ciprofibrate,” Drugs under Experimental and Clinical Research, vol. 26, no. 3, pp. 83–88, 2000. View at: Google Scholar
  18. P. Colville-Nash, D. Willis, J. Papworth et al., “The peroxisome proliferator-activated receptor α activator, Wy14,643, is anti-inflammatory in vivo,” Inflammopharmacology, vol. 12, no. 5-6, pp. 493–504, 2004. View at: Publisher Site | Google Scholar
  19. G. Chinetti, J.-C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation,” Inflammation Research, vol. 49, no. 10, pp. 497–505, 2000. View at: Publisher Site | Google Scholar
  20. P. Delerive, P. Gervois, J.-C. Fruchart, and B. Staels, “Induction of IκBα expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-α activators,” The Journal of Biological Chemistry, vol. 275, no. 47, pp. 36703–36707, 2000. View at: Publisher Site | Google Scholar
  21. C. Jiang, A. T. Ting, and B. Seed, “PPAR-γ agonists inhibit production of monocyte inflammatory cytokines,” Nature, vol. 391, no. 6662, pp. 82–86, 1998. View at: Google Scholar
  22. M. Kockx, P. P. Gervois, P. Poulain et al., “Fibrates suppress fibrinogen gene expression in rodents via activation of the peroxisome proliferator-activated receptor-α,” Blood, vol. 93, no. 9, pp. 2991–2998, 1999. View at: Google Scholar
  23. R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula, “The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses,” The Journal of Immunology, vol. 164, no. 3, pp. 1364–1371, 2000. View at: Google Scholar
  24. R. Cunard, D. DiCampli, D. C. Archer et al., “WY14,643, a PPARα ligand, has profound effects on immune responses in vivo,” The Journal of Immunology, vol. 169, no. 12, pp. 6806–6812, 2002. View at: Google Scholar
  25. R. Cunard, M. Ricote, D. DiCampli et al., “Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors,” The Journal of Immunology, vol. 168, no. 6, pp. 2795–2802, 2002. View at: Google Scholar
  26. R. Cunard, Y. Eto, J. T. Muljadi, C. K. Glass, C. J. Kelly, and M. Ricote, “Repression of IFN-γ expression by peroxisome proliferator-activated receptor γ,” The Journal of Immunology, vol. 172, no. 12, pp. 7530–7536, 2004. View at: Google Scholar
  27. K. Uchimura, M. Nakamuta, M. Enjoji et al., “Activation of retinoic X receptor and peroxisome proliferator-activated receptor-γ inhibits nitric oxide and tumor necrosis factor-α production in rat Kupffer cells,” Hepatology, vol. 33, no. 1, pp. 91–99, 2001. View at: Publisher Site | Google Scholar
  28. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at: Publisher Site | Google Scholar
  29. X. Y. Yang, L. H. Wang, T. Chen et al., “Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor γ (PPARγ) agonists. PPARγ co-association with transcription factor NFAT,” The Journal of Biological Chemistry, vol. 275, no. 7, pp. 4541–4544, 2000. View at: Publisher Site | Google Scholar
  30. N. Marx, B. Kehrle, K. Kohlhammer et al., “PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis,” Circulation Research, vol. 90, no. 6, pp. 703–710, 2002. View at: Publisher Site | Google Scholar
  31. R. Di Paola, E. Esposito, E. Mazzon et al., “Absence of peroxisome proliferators-activated receptors (PPAR)α enhanced the multiple organ failure induced by zymosan,” Shock, vol. 26, no. 5, pp. 477–484, 2006. View at: Google Scholar
  32. P. R. Devchand, H. Keller, J. M. Peters, M. Vazquez, F. J. Gonzalez, and W. Wahli, “The PPARα–leukotriene B4 pathway to inflammation control,” Nature, vol. 384, no. 6604, pp. 39–43, 1996. View at: Publisher Site | Google Scholar
  33. J. M. Peters, N. Hennuyer, B. Staels et al., “Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor α-deficient mice,” The Journal of Biological Chemistry, vol. 272, no. 43, pp. 27307–27312, 1997. View at: Publisher Site | Google Scholar
  34. S. P. Anderson, L. Yoon, E. B. Richard, C. S. Dunn, R. C. Cattley, and J. C. Corton, “Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice,” Hepatology, vol. 36, no. 3, pp. 544–554, 2002. View at: Publisher Site | Google Scholar
  35. T. Hashimoto, W. S. Cook, C. Qi, A. V. Yeldandi, J. K. Reddy, and M. S. Rao, “Defect in peroxisome proliferator-activated receptor α-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting,” The Journal of Biological Chemistry, vol. 275, no. 37, pp. 28918–28928, 2000. View at: Publisher Site | Google Scholar
  36. S. L. Friedman, “Liver fibrosis—from bench to bedside,” Journal of Hepatology, vol. 38, pp. 38–53, 2003. View at: Publisher Site | Google Scholar
  37. S. L. Friedman, “Hepatic stellate cells,” Progress in Liver Diseases, vol. 14, pp. 101–130, 1996. View at: Google Scholar
  38. T. Miyahara, L. Schrum, R. Rippe et al., “Peroxisome proliferator-activated receptors and hepatic stellate cell activation,” The Journal of Biological Chemistry, vol. 275, no. 46, pp. 35715–35722, 2000. View at: Publisher Site | Google Scholar
  39. S. Hazra, V. Krishna, K. Chatterjee, R. A. Rippe, and H. Tsukamoto, “PPARγ dependent regulation of hepatic stellate cells,” Hepatology, vol. 36, no. 4, p. 255A, 2002. View at: Google Scholar
  40. F. Marra, E. Efsen, R. G. Romanelli et al., “Ligands of peroxisome proliferator-activated receptor γ modulate profibrogenic and proinflammatory actions in hepatic stellate cells,” Gastroenterology, vol. 119, no. 2, pp. 466–478, 2000. View at: Publisher Site | Google Scholar
  41. A. Galli, D. W. Crabb, E. Ceni et al., “Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro,” Gastroenterology, vol. 122, no. 7, pp. 1924–1940, 2002. View at: Publisher Site | Google Scholar
  42. T. Toyama, H. Nakamura, Y. Harano et al., “PPARα ligands activate antioxidant enzymes and suppress hepatic fibrosis in rats,” Biochemical and Biophysical Research Communications, vol. 324, no. 2, pp. 697–704, 2004. View at: Publisher Site | Google Scholar
  43. S. Dharancy, M. Malapel, G. Perlemuter et al., “Impaired expression of the peroxisome proliferator-activated receptor alpha during hepatitis C virus infection,” Gastroenterology, vol. 128, no. 2, pp. 334–342, 2005. View at: Publisher Site | Google Scholar
  44. A. de Gottardi, V. Pazienza, P. Pugnale et al., “Peroxisome proliferator-activated receptor-α and -γ mRNA levels are reduced in chronic hepatitis C with steatosis and genotype 3 infection,” Alimentary Pharmacology & Therapeutics, vol. 23, no. 1, pp. 107–114, 2006. View at: Publisher Site | Google Scholar
  45. T. Kurihara, A. Niimi, A. Maeda, M. Shigemoto, and K. Yamashita, “Study of effectiveness of bezafibrate in the treatment of chronic hepatitis C,” The American Journal of Gastroenterology, vol. 96, no. 5, pp. 1659–1660, 2001. View at: Publisher Site | Google Scholar
  46. N. Fujita, M. Kaito, H. Tanaka, S. Horiike, and Y. Adachi, “Reduction of serum HCV RNA titer by bezafibrate therapy in patients with chronic hepatitis C,” The American Journal of Gastroenterology, vol. 99, no. 11, p. 2280, 2004. View at: Publisher Site | Google Scholar

Copyright © 2009 Sébastien Dharancy et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Related articles

No related content is available yet for this article.
 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

No related content is available yet for this article.

Article of the Year Award: Outstanding research contributions of 2021, as selected by our Chief Editors. Read the winning articles.