Cellular Signalling 24 (2012) 596–605

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Cellular Signalling

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Review

Peroxisome proliferator-activated receptor-γ cross-regulation of signaling eventsimplicated in liver fibrogenesis

Feng Zhang a, Yin Lu a,b, Shizhong Zheng a,b,⁎a Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210029, Chinab Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China

Abbreviations: AdipoR, adiponectin receptor; AMPK,B; Cidea, mitochondrial cell death-inducing DNA fragmeearly growth response-1; ERK, extracellular signal-reguLXR-α, liver X receptor-α; MAPK, mitogen-activated prrived growth factor; PI3K, phosphatidylinositol-3-kinasreceptor-α; SA-β-gal, senescence-associated β-galactoelement-binding proteins-1c; STAT3, signal transducerToll-like receptor; TNF, tumor necrosis factor; TRAIL-R,⁎ Corresponding author at: Department of Clinical Ph

Tel.: +86 25 86798154; fax: +86 25 86798188.E-mail address: nytws@163.com (S. Zheng).

0898-6568/$ – see front matter © 2011 Elsevier Inc. Alldoi:10.1016/j.cellsig.2011.11.008

a b s t r a c t

a r t i c l e i n f o

Article history:Received 11 October 2011Accepted 2 November 2011Available online 13 November 2011

Keywords:Peroxisome proliferator-activated receptor-γLiver fibrosisHepatic stellate cellSignal transductionCross-regulation

Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear receptor with transcriptional activitycontrolling multiple physical and pathological processes. Recently, PPARγ has been implicated in thepathogenesis of liver fibrosis. Its depleted expression has strong associations with the activation andtransdifferentiation of hepatic stellate cells, the central event in liver fibrogenesis. Studies over the pastdecade demonstrate that PPARγ cross-regulates a number of signaling pathways mediated by growth fac-tors and adipokines, and cellular events including apoptosis and senescence. These signaling and cellularevents and their molecular interactions with PPARγ system are profoundly involved in liver fibrogenesis.We critically summarize these mechanistic insights into the PPARγ regulation in liver fibrogenesis basedon the updated findings in this area. We conclude with a discussion of the impacts of these discoveries onthe interpretation of liver fibrogenesis and their potential therapeutic implications. PPARγ activationcould be a promising strategy for antifibrotic therapy.

© 2011 Elsevier Inc. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5972. Role of PPARγ in liver fibrogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5973. PPARγ crosstalk with growth factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598

3.1. Transforming growth factor-β signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5983.2. Platelet-derived growth factor signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5993.3. Hepatocyte growth factor signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 599

4. PPARγ crosstalk with adipokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5994.1. Leptin signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5994.2. Adiponectin signaling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 600

5. PPARγ modulation of apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6005.1. The extrinsic pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6005.2. The intrinsic pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 601

6. PPARγ modulation of cellular senescence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6017. Implications and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 602Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603

5′-AMP-activated protein kinase; AP1, activator protein 1; C/EBP, CCAAT/enhancer binding protein; CHB, chronic hepatitisntation factor α-like effector A; CTGF, connective tissue growth factor; DR, death receptor; ECM, extracellular matrix; Egr-1,lated kinase; HGF, hepatocyte growth factor; HSC, hepatic stellate cell; JAK2, Janus kinase 2; JNK, c-Jun N-terminal kinase;otein kinase; NF-κB, nuclear factor-κB; NIK, NF-κB-inducing kinase; ObR, obese gene product receptor; PDGF, platelet-de-e; PPAR, peroxisome-proliferator activated receptor; PPRE, peroxisome proliferator response elements; RXR-α, retinoid Xsidase; SIRT1, silent information regulator type 1; SMP30, senescence marker protein 30; SREBP-1c, sterol regulatoryand activator of transcription 3; TβR, transforming growth factor-β receptor; TGF-β, transforming growth factor-β; TLR,TNF related apoptosis-inducing ligand receptor.armacy, College of Pharmacy, Nanjing University of Chinese Medicine, 282 Hanzhong Road, Nanjing, Jiangsu 210029, China.

rights reserved.

597F. Zhang et al. / Cellular Signalling 24 (2012) 596–605

Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 603

1. Introduction

Peroxisome-proliferator activated receptors (PPARs) belong to thesuperfamily of nuclear hormone receptors. To date, four isoforms ofPPARs have been identified, namely PPARα, β, γ and δ, which regulatetranscription of a number of target genes controlling many importantphysiological processes [1]. There are twomajor forms of PPARγ, name-ly γ1 and γ2, resulting from alternate promoter usage and splicing [2].PPARγ structurally comprises a central DNA-binding domain, a carboxyterminal ligand-binding domain and two transcription activation func-tionmotifs termed AF-1 and AF-2 [3]. The core of PPARγ ligand-bindingsite is a large Y-shaped cavity composedof 12α-helices located at the C-terminal, which functions as a molecular switch and ligand binding towhich is required for full agonist activity toward PPARγ [4]. In theabsence of ligands, PPARγ interacts with the co-repressor proteinsand inhibits gene expression. Upon binding to cognate ligands, PPARγdissociates the co-repressor and translocates from cytoplasm to thenucleus where it recruits co-activator proteins and forms a heterodimerwith retinoid X receptor-α (RXR-α). The multiprotein complex thenbinds to peroxisome proliferator response elements (PPRE), the specificDNA sequences in target gene promoter, leading to transcriptionalactivation [5]. Posttranslational modifications such as phosphorylation[6], sumoylation [7] or ubiquitination [8] may also modulate thetranscription activity of PPARγ.

PPARγ is expressed in various tissues and cell types, mainly inadipose tissue, where it regulates adipocyte differentiation andglucose homestasis [9]. PPARγ activation by its endogenous ligandssuch as fatty acids initiates transcription of adipogenesis-associatedtarget genes, such as FABP4 (which encodes fatty acid-binding protein4) and CD36 (which encodes fatty acid translocase) [10]. Moreover,PPARγ plays a pivotal role in metabolic syndrome through geneticcorrelation with insulin resistance and type 2 diabetes mellitus,because it is a key regulator of insulin sensitivity and the drug targetof synthetic thiazolidinedione agents against type 2 diabetes. PPARγactivation ameliorates hyperglycemia and dyslipidemia in diabetesdue to its insulin sensitization capability [11].

Fig. 1. This diagram represents the mode for PPARγ-mediated gene transcription and the bioprotein complex with RXRα and co-activators in the nucleus. The complex binds to the Presponse element sequence AGGTCA separated by one base pair (indicated as X), and learange of pathophysical processes including adipocyte differentiation, glucose homeostasis,regulation, and tissue repair program. The anti-inflammatory properties and the beneficialliver fibrosis therapy.

Increasing understanding toward PPARγ biology demonstratesthat this transcription factor has pleiotropic functions in variousfundamental pathways with more wide-ranging pathophysiologicalimplications. PPARγ is shown to be involved in circadian regulatorysystem [12] and bone marrow adipogenesis [13]. PPARγ is alsoimplicated in cell-fate determination in a variety of cell types, forinstance, ligand activation of PPARγ can result in growth inhibitionor apoptosis in fibroblasts [14] and several kinds of cancer cells [15, 16].Recently, much attention has been paid to the anti-inflammatory andprotective effects of PPARγ during tissue repair program. PPARγregulates gene transcriptions involved in the wound-healing processof many organs, and thereby ameliorates inflammation, oxidativestress, and matrix remolding in the injured tissue [17]. Mode forPPARγ-mediated gene transcription and the biological consequencesare illustrated in Fig. 1. Furthermore, perhaps a breakthrough in under-standing PPARγ pathophysiology over the past decade could be therecognition that PPARγ acts as a pivotal molecular in liver fibrogenesis.Its transcriptional dysfunction and interplay with a series of signalingevents that are involved in fibrogenesis underlie the molecularpathogenesis of liver fibrosis [18]. Accumulating knowledge in thisfacet provides novel insights into the signal transduction-basedpharmacological intervention of liver fibrosis, a widespread disorderfor which effective therapies are still lack in current clinical context. Inthis review, we will first briefly describe the basic principles of liverfibrogenesis and the newly uncovered role of PPARγ in this pathology,and then critically discuss the updated findings on how PPARγ interactswith the primary signaling events implicated in liver fibrogenesis.

2. Role of PPARγ in liver fibrogenesis

Liver fibrogenesis is defined as a dynamic wound-healing processcharacterized by excessive production and deposition of extracellularmatrix (ECM) mainly type I collagen in the liver. The ECM depositiondistorts hepatic sinusoids and compromises hepatocyte function. It iswell-established that activation of hepatic stellate cells (HSCs), a typeof nonparenchymal cell resident in the space of Disse, is the central

logical outcomes. PPARγ activated by endogenous or exogenous ligands forms a multi-PRE in the promoter region of target genes, which is a direct repeat of the hormoneds to transcriptional activation. The PPARγ transactivation has impacts upon a widecircadian rhythm system, skeleton metabolism, cell-fate determination, inflammatoryeffects in wound-healing process may imply the important role for PPARγ system in

598 F. Zhang et al. / Cellular Signalling 24 (2012) 596–605

event in liver fibrogenesis [19]. Normally, HSCs are quiescent andstores up to 85% of the body's total vitamin A content in their lipiddroplets. Upon injury, they are activated and undergo transdifferen-tiation from non-proliferating cells to myofibroblasts responsible forthe overproduction of collagen-rich ECM. Meanwhile, the lipid drop-lets and vitamin A contents are diminished rapidly, exhibiting a dele-tion of adipogenic phenotype [20].

Advances in understanding the molecular mechanisms underlyingHSC activation and liver fibrogenesis suggest the involvement ofcomplex signaling modulations performed by a number of cytokinesand chemokines within HSCs or between HSCs and other cell types[21]. Transcriptional factor PPARγ has been identified to be thecentral regulator of these signaling events and functions as a switchmolecular for HSC activation and phenotype alteration [22]. Therehas been clear evidence that HSC activation was accompanied bysignificantly decreased PPARγ expression, whereas ectopic PPARγexpression or PPARγ ligands reversed the biochemical features ofHSC activation and reduced collagen secretion both in vitro and invivo [23–25]. Mechanistic investigations showed that PPARγ main-tained HSC quiescence through regulating a panel of adipogenic tran-scription factors, including CCAAT/enhancer binding protein (C/EBP),liver X receptor-α (LXRα), and sterol regulatory element-bindingproteins-1c (SREBP-1c), whichwere rapidly depleted duringHSC trans-differentiation [26]. Moreover, adipogenic transcriptional regulation inHSCs by PPARγ also occurred at the level of chromatin packaging,because DNAmethylation inhibitor blocked HSC myofibroblastic trans-differentiation andprevented the diminished PPARγ expression inHSCs[27]. Collectively, these discoveries preliminarily address the adipo-genicmechanisms of PPARγ in HSC activation and suggest the antifibro-tic role of PPARγ activation. Indeed, ectopic PPARγ expression andPPARγ agonists have exhibited therapeutic benefits for experimentalliver fibrosis in various animal models [28–30]. And thiazolidinedionePPARγ ligands have been undergoing clinical evaluation for theirtherapeutic efficacy and safety as therapies against chronic liver diseasesincluding fibrosis in humans [31].

Although the precise molecular mechanisms underlying the antifi-brotic potential of PPARγ system remain largely unknown, it is highlypossible that the PPARγ interactions with a series of signaling pro-cesses that regulate HSC expression of fibrogenic molecules and thedynamic balance between HSC proliferative and apoptotic statuscould account for the pivotal role of PPARγ in liver fibrogenesis. Thepast decade has indeed witnessed tremendous advances in thisresearch area. In the following sections, we will survey the currentknowledge on PPARγ cross-regulation of the key fibrosis-relatedsignaling events. Of note is that some findings discussed below arenot restricted to the pathology of liver fibrosis due to limited litera-ture data, but we hold that they are relevant information of signifi-cance and can illuminate the interpretation of liver fibrosis andguide the development of antifibrotics.

3. PPARγ crosstalk with growth factors

3.1. Transforming growth factor-β signaling

A variety of cell types produce transforming growth factor-β (TGF-β) that consists of three major isoforms, namely β1, β2 and β3. TGF-β1 is the principal isoform implicated in liver fibrosis. TGF-β1 isstored as an inactivated form bound to a latency-associated protein.Following activated in liver injury, TGF-β1 initiates its fibrogenic sig-naling cascade by binding to the type I and type II surface receptors(TβRI and TβR II), which belong to the family of receptor serine/threonine kinase, leading to phosphorylation of Smad2 and Smad3,and allowing Smad2/3 to associate with the common mediator Smad4.Subsequently, the Smad heterodimers translocate into the nucleus andtrigger target gene transcription, including collagens I and III. The inhib-itory Smad6/7 can disrupt the binding of Smad2/3 to the receptor,

constituting an endogenous suppression of the transduction [32]. Acti-vated HSCs express TGF-β1 and Smads 2, 3, 4, and 7, and the levels ofTGF-β1 and Smads 2 and 4 increase as fibrosis progresses, but Smad7expression is in silence, leaving Smads 2, 3 and 4 to promote the fibroticresponses [33]. Moreover, Smad3 knockout resulted in decreasedcollagen I production and attenuated HSC proliferation [34]; where-as forced expression of Smad7 blocked HSC transdifferentiation dueto inhibited Smad2/3 phosphorylation [35]. There are also reportsshowing the involvement of TβRII/Smad1/ERK pathway [36], theTGF-β-induced collagen stability via p38 activity [37], and the profi-brogenic role of Nogo-B via facilitating TGF-β/Smad2 signaling inliver fibrogenesis [38].

A number of literature data support a direct role for PPARγ inmodulation of TGF-β/Smads signaling. PPARγ could abrogate TGF-β/Smad stimulation of transcriptional responses and collagen geneexpression in the profibrotic myofibroblasts [39]. PPARγ activationalso abrogated TGF-β-induced promoter activity of connective tissuegrowth factor (CTGF), a key molecular amplifying the profibrogenicresponses in the fibrotic liver [40, 41], but this suppression could becompletely rescued by Smad3 overexpression but not Smad4 [42].This was the first evidence that CTGF is a PPARγ-regulated gene viaTGF-β/Smad3 signaling pathway. Ligand activation of PPARγ alsopotently inhibited CTGF expression in rat HSCs by disrupting TGF-β1 signaling [43], and inhibited TβRI/Smad3-mediated inductionof ECM gene expression in cultured human HSCs [44]. However,the PPARγ ligands probably affected neither the Smad2/3 proteinlevel nor Smad2/3 phosphorylation under these conditions. Thismay give rise to a hypothesis that activated PPARγ triggers its asso-ciation with certain nuclear receptor co-activators, then becomingrepressive for Smad-mediated transcription. Indeed, there has beenpreliminary proof that transcriptional co-activator p300, also a histoneacetyltransferase, participated in PPARγ-mediated inhibition of TGF-β/Smad signaling [45]. Consistent with this, Ghosh et al. demonstratedthat PPARγ disrupted Smad-mediated transcriptional pathway byblocking p300 recruitment and histone H4 hyperacetylation, leadingto suppression of TGF-β-induced collagen gene expression in humanfibroblasts [46]. These results suggest PPARγ-mediated inhibition ofp300-Smad2/3 association as a novel mechanism underlying PPARγmodulation of TGF-β/Smad profibrotic responses. Moreover, PPARγwas shown to disrupt the binding of TGF-β1-activated Smads to theirresponse elements [47], indicating that PPARγ transrepression towardTGF-β signaling may also occur at the level of specific mediators of thepathway, such as Smads. On the other hand, some details of how TGF-β affects PPARγ system have also been elucidated. Fu et al. proposedthat TGF-β initially stimulated PPARγ expression via ERK/Egr-1 (earlygrowth response-1) signaling, whereas late inhibited PPARγ expres-sion via activator protein 1 (AP1) and Smad3, and possibly NAB2 [48].Collectively, these findings provide important information on the cross-talk between PPARγ and TGF-β signaling. It would be interesting toenvision that these molecular linkings are potential pharmacologi-cal targets for fibrosis therapy, but one should consider how to re-press the fibrogenic activities of TGF-β in HSCs while retaining theother beneficial effects of TGF-β in the injured liver such as theanti-inflammatory property and its function as an important regula-tor of hepatocyte proliferation [49].

We recently demonstrated that natural polyphenolic compoundcurcumin significantly reduced the expression of TβRI and TβRII in aPPARγ activation-dependent manner, leading to TGF-β signalingdisruption in HSCs and potent antifibrotic effects. In addition, curcu-min activation of PPARγ abrogated TGF-β-induced CTGF expression[50–52]. These data are consistent with the aforementioned discoverieson the PPARγ crosstalk with TGF-β signaling and imply that pharmaco-logical intervention via PPARγ activation can indeed block the profibro-genic TGF-β/Smad pathway, and thereby inhibit HSC activation andtreat hepatic fibrosis. Actually, the safety of curcumin for human usehas been demonstrated by clinical evidence in some other pathological

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contexts [53]. More basic and clinical studies are needed to recom-mend this natural PPARγ ligand for human liver disease therapy.

3.2. Platelet-derived growth factor signaling

Platelet-derived growth factor (PDGF) is another key fibrogenicstimulus to HSC activation and hepatic fibrogenesis. PDGF is structurallyidentified as a disulfide-linked dimeric protein composed of varyingcombinations of four polypeptide chains (A, B, C, and D). PDGF trans-mits its signal via the tyrosine kinase receptors PDGF-αR or -βR andthe downstream mitogen-activated protein kinase (MAPK) cascadesincluding extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 [54]. In liver, quiescentHSCs are negativefor PDGF-βR,whose expression, however, is significantly upregulated inactivated HSCs both in vitro and in vivo, rendering HSCs highly respon-sive to PDGF-B [54]. Recently, PDGF-C and -D have also been linked toliver fibrogenesis in two in vivo studies, where PDGF-C overexpressionled to fibrosis and hepatocellular carcinoma [55], and PDGF-Dsignificantly facilitated HSC proliferation and ECM expression [56].

Although numerous studies have described how PPARγ activity isregulated by receptor tyrosine kinases [57], information on PPARγregulation of PDGF/MAPK pathway is newly emerging. It was foundthat PDGF signaling led to progressive reduction in PPRE reporteractivity; whereas natural and synthetic PPARγ ligands or transfectionwith PPARγ repressed PDGF-induced human HSC proliferation inculture [24, 58]. Activation of PPARγ by ligands also inhibited ERKactivity and PDGF-induced c-Fos promoter activity, suggesting thatPPARγ affected PDGF/MAPK pathway [59]. Moreover, some otherstudies covering a variety of pathological situations demonstratedthe repression of PPARγ toward JNK signaling [60], and p38 MAPKpathway [61]. However, there is also evidence that PPARγ ligandscould activate MAPK pathway independently of PPARγ [62]. Thus, itcould be a little bit hard to give a clear overview on the molecularbasis for PPARγ ligand regulation of PDGF/MAPK signaling implicatedin liver fibrotic responses, but this issue should be addressed withmuch importance, because it implies potential therapeutic interven-tions. Indeed, PDGF-kinase inhibitor imatinib was shown to be prom-ising for treating liver fibrosis [63]. Additionally, the naturalantifibrotic curcumin dependent on PPARγ activation interruptedPDGF signaling in activated HSCs by reducing PDGF-βR phosphoryla-tion and gene expression, and suppressing its downstream cascadesincluding ERK1/2 and JNK1/2 [64]. These results not only furtherelucidate the mechanisms of curcumin for inhibition of HSC activa-tion and blockade of hepatic fibrogenesis, but also provide newinsights into the implications of PPARγ interaction with PDGF/MAPKpathway in liver fibrosis.

3.3. Hepatocyte growth factor signaling

Hepatocyte growth factor (HGF) is originally identified as apowerful mitogen for hepatocytes. HGF stimulates cellular growthand motility, and morphogenesis through activating its specific tyro-sine kinase receptor known as c-Met (an oncogene product) at cellsurface [65]. HGF/c-Met system plays an essential role in liver devel-opment and regeneration, and its disruption affects hepatocytesurvival and tissue remodeling [66]. Unlike TGF-β and PDGF dis-cussed above, HGF has emerged as a cytokine that potently preventsliver fibrogenesis. There has been in vivo evidence that HGFsuppressed liver fibrosis by reducing HSC activation and collagensynthesis, and promoted liver recovery from chronic injuries in distinctanimalmodels [67–69]. HGF-mediated antifibrosis is probably attribut-ed to disruption of profibrogenic TGF-β signaling including decreasedexpression of TGF-β1 and its receptor and inhibited Smad2/3 nucleartranslocation. In addition, HGF was found to enhance the interactionof phosphorylated Smad3 with galectin-7 that inhibited TGF-β-

stimulated COL1A2 and plasminogen activator inhibitor-1 transcrip-tion in activated HSCs [70].

Increasing studies have suggested PPARγ regulation of HGF/c-Metsignaling system. Although it is known that regulation of HGF geneexpression involves a number of transcription factors such as COUP-TF, C/EBP, estrogen receptor, nuclear factor-1, and AP2 [71–73], aPPARγ responsive element was also found to localize upstream fromthe transcription start site of HGF gene promoter and played a crucialrole. Ligand activation of PPARγ strongly stimulated HGF promoteractivity, and induced HGF mRNA and protein expression in fibroblasts[74]. This provided clear evidence that HGF is a target gene of PPARγ.HGF expression induced by PPARγ agonists was also observed inother pathological contexts of tissue injury [75]. Furthermore, PPARγplayed a role in HGF-mediated disruption of TGF-β signaling implicatedin liver fibrogenesis, because PPARγ activation promoted c-Met recep-tor phosphorylation, upregulated expression of TG-interacting factor,a Smad transcriptional co-repressor, and suppressed Smad-mediatedgene transcription, suggesting novel mechanisms that couple PPARγ,HGF, and TGF-β/Smad signaling [76].

Although to address how PPARγ mediates the antifibrotic poten-tial of HGF signaling requires more illuminating evidence in vivo, HGFgene therapy has indeed shown therapeutic benefits in a series of ani-mal studies through various delivery methods such as transfection ofhuman HGF gene into skeletal muscles [77], infusion of plasmid DNAvia portal vein followed by electroporation [78], transfection withHGF-expressing adeno-associated virus vectors [79], or transfectionwith human HGF naked plasmid DNA [80]. Fibrogenic makers andcollagen synthesis were all significantly suppressed under theseconditions. Since PPARγ activation can directly stimulate HGF/c-Metsystem, it would be attractive to suggest a therapeutic approachcombining HGF gene therapy and small molecule PPARγ agonistsfor synergistic effects. This may hold promise in manipulation ofliver fibrosis worthy of further investigations.

4. PPARγ crosstalk with adipokines

4.1. Leptin signaling

Adipokines are polypeptide cytokines predominantly secreted inadipose tissue by a regulated pattern. The obese gene product leptinis a best-investigated adipokine actively involved in liver fibrogenesis.Leptin transmits its biological activity through leptin receptors (ObRs),which consist of six isoforms, and downstream Janus kinase 2 (JAK2)signal transducer and activator of transcription 3 (STAT3) pathway[81]. A number of investigations in vitro [82, 83] and in vivo [84, 85]demonstrated that leptin is a potent stimulator for HSC profibrogenicbehaviors, including increased proliferation, prevented apoptosis, colla-gen overproduction, and upregulated proinflammatory and proangio-genic cytokines. Leptin also induces HSC phagocytosis, during whichRho-guanosine triphosphate-ases mediate the cytoskeleton regulation,suggesting a novel role for leptin responsible for fibrogenic process [86].In addition, leptin also activates kupffer cells and macrophages, andstimulates hepatic sinusoid endothelial cells to secrete TGF-β [87].

The critical role of PPARγ in lipometabolism makes it relevantto adipokine signal transductions. Indeed, several in vivo studiesdemonstrated PPARγ involvement in leptin signaling in variousphysiopathological conditions. Leptin stimulated expression of PPARγco-activator-1 [88], and enhanced hepatic triglyceride content associ-ated with fat-specific protein 27 that is a PPARγ target gene [89].Recently, evidence in vitro showed that leptin downregulatedPPARγ gene expression by activating phosphatidylinositol-3-kinase(PI3K)/AKT or ERK pathway in rat HSCs [90] and Egr-1 was involvedin suppressed PPARγ expression by leptin [91]. Leptin also suppressedPPARγ protein expression in HSCs potentially through leptin-inducedERK1/2 activation in vivo [92].

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Compelling evidence has also highlighted the PPARγ modulationof leptin signaling. Activation of PPARγ by thiazolidinediones inhib-ited leptin expression in cell culture system [93] and rodent models[94]. Thiazolidinedione-induced leptin suppression was shown to beassociated with PPARγ antagonism to C/EBP-α on at least two sepa-rate promoters of leptin at the transcriptional level [95]. Furthermore,PPARγ ligand ciglitazone diminished ObR expression in leptin-activated human HSCs potentially associated with suppression ofERK activation, but it failed to reverse leptin-induced inhibition ofSREBP-1c expression presumably because mere PPARγ ligand mightnot sufficiently activate PPARγ to the extent of changing SREBP-1cmRNA level [96]. Although the in vivo evidence for PPARγ interactionwith leptin signaling in the context of liver fibrogenesis is eagerlyawaited so far, clinical data has indicated the correlation betweenPPARγ gene expression (both γ1 and γ2 isoform) and leptin secretionin humans [97]. These insights provide rationale for developing noveltherapeutics targeting PPARγ/leptin system for liver fibrosis therapy.Indeed, the natural PPARγ agonist curcumin has recently been shownto protect HSCs against leptin-induced activation, making it a morepromising therapeutic candidate for the management of hepaticfibrosis in obese patients [98].

4.2. Adiponectin signaling

Adiponectin and its receptor (AdipoR) represent a new adipokinesystem involved in liver fibrogenesis. Adiponectin structurally containsa collagen-like domain connecting to a globular moiety that retains thefunctional significance after cleavage. Adiponectin bioactivity is mostlyattributed to the high-molecular weight form rather than the full-length adiponectin [99]. Two specific receptors, namely AdipoR1 andAdipoR2, serve as transducers for globular and full-length adiponectin,respectively, but which isoform is more susceptible to adiponectinremains to be defined [100]. Contrary to its adipokine counterpartleptin, adiponectin is a beneficial molecular for hepatic inflammationand fibrosis. Adiponectin knockout led to severe liver fibrogenesiswith elevated TGF-β1 and CTGF expression in animals [101]. Themech-anisms underlying the antifibrogenic effects of adiponectin includeinduction of caspase-dependent apoptosis in activated HSCs [100],upregulation of 5′-AMP-activated protein kinase (AMPK) and subse-quent inhibition of AKT pathway [102], activation of mitochondrialrespiratory chain complexes involving uncoupling protein 2 [103], andrecruitment and phenotype polarization of kupffer cells [104].

PPARγ also plays a role in regulation of adiponectin expressionand secretion. PPRE was identified to be present in human adiponec-tin promoter [105], and PPARγ agonists could induce transactivationof adiponectin promoter [106]. Adiponectin expression induced byPPARγ ligands required PPARγ2 isoform rather than C/EBPα in vitro[107], and involved activation of AMPK pathway in vivo [108]. In thecontext of metabolic syndrome, PPARγ agonist rosiglitazone wasfound to result in significantly increased adiponectin gene expressionin rodents [109]. PPARγ agonists MK-0767 [110] and pioglitazone [111]could also improve adiponectin secretion and sensitivity in humans.Population genetic analysis further indicated that the Pro12Alapolymorphism of the PPARγ gene might influence the serum level ofadiponectin in humans [112, 113]. In the context of liver pathology, itwas recently reported that ligand activation of PPARγ was unable tohalt HSC activation in HSCs genetically lacking adiponectin, suggestingadiponectin as a major downstream effector for PPARγ actions; howev-er, adiponectin-induced inhibition of HSC activation could be PPARγ-independent, because adiponectin overexpression in PPARγ-null HSCssuppressed collagen expression in the absence of PPARγ [114]. Thesefindings highlight a complicated relationship between PPARγ andadiponectin in HSC activation. Further investigations are needed toelucidate the mechanisms responsible for these observations.

How endogenous PPARγ associates with adiponectin is increasinglyunderstood. PPARγ could be negatively regulated by poly(ADP-ribose)

polymerase 1, which in turn contributed to the inhibited expression ofadiponectin and AdipoR1 in cardiac fibroblasts [115]. In addition,PPARγ suppressed the transcriptional activity of endoplasmic reticulump44, which increased adiponectin secretion in human embryonickidney cells [116]. Intriguingly, PPARγ together with its endogenousligands was recently found to mediate the vitamin E-induced adipo-nectin expression in 3T3-L1 cells [117]. What implications of thesefindings in the pathology of liver fibrosis are largely unknown, butshould be further investigated as they may be instrumental for thera-peutic interventions of liver fibrosis given the antifibrotic potential ofboth PPARγ and adiponectin. Surprisingly, adiponectin and PPARγagonist rosiglitazone were recently indicated to promote HBV replica-tion in vitro, suggesting that control of adiponectin might be a thera-peutic modality for treatment of chronic hepatitis B (CHB) [118]. Thisprobably creates a dilemma for adiponectin use in chronic liverdisease therapy considering the higher risk of CHB progressing tofibrosis.

5. PPARγ modulation of apoptosis

Apoptosis is highly regulated cell death biochemically character-ized by nuclear fragmentation, chromatin condensation, membranealterations, and cell shrinkage. Apoptosis is trigged primarily throughthe extrinsic and intrinsic pathways, two mutually inclusive signal-ings. The two pathways share common downstream effectors calledcaspases, a group of cysteine proteases acting as ultimate executorsof apoptosis [119]. Caspase-independent apoptosis also exists [120].We here do not describe the general mechanisms of apoptosis (forreview [121]), but focus on the apoptosis in the pathogenesis ofliver fibrosis. Fibrogenesis is concomitant with significant hepato-cyte apoptosis [122], whereas HSC apoptosis contributes to fibrosisregression [123], and thus HSC apoptosis-inducing strategy has highpotential to reverse liver fibrosis [124]. PPARγ-regulated apoptosisis a critical cellular event implicated in liver fibrosis.

5.1. The extrinsic pathway

The extrinsic cascade of apoptosis is initiated by membrane-bounddeath receptors (DRs), including Fas, tumor necrosis factor receptor1 (TNF-R1), and TNF related apoptosis-inducing ligand receptor 1and 2 (TRAIL-R1 and -R2), binding to their ligands FasL, TNF-α,and TRAIL. Then the adaptor Fas-associated protein with deathdomain is recruited to form the death-induced signaling complex,which subsequently activates caspase-8 and -3 in sequence [125].Death receptors and their ligands are ubiquitously expressed inliver, thus the apoptotic machinery in liver fibrosis is commonlytriggered through the extrinsic pathway [126]. Activation of Fasand TNF-R1 is particularly associated with hepatocyte apoptosis inchronic liver injury [122]. TNF-α binding to TNF-R1 also activatesnuclear factor-κB (NF-κB), a transcription factor for production ofmany pro-inflammatory cytokines, and further amplifies liver injury[127]. TRAIL-R2 is not expressed on hepatocytes, but is preferentiallyupregulated in activated HSCs, rendering them susceptible to TRAIL-mediated apoptosis [128]. This indicates that induction of apoptosisusing TRAIL-R2 agonistic antibody may selectively kill HSCs. Fas/Fas-ligand-dependent mechanism was also found in HSC apoptosis[129].

PPARγ system has molecular associations with the signalingsmediated by death ligands. TNF-α suppressed the PPARγ transactiva-tion induced by ligands via NF-κB that was activated by the TAK1/TAB1/NIK (NF-κB-inducing kinase) cascade in osteoblasts [130].TNF-α also induced protein cleavage of PPARγ in a caspase-dependent manner in adipocytes, leading to disrupted nuclear locali-zation of PPARγ [131]. Conversely, ligand activation of PPARγ wasfound to inhibit TNF-α expression and the downstream cascade

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such as NF-κB transcriptional activity in a variety of culture system[132–134].

Two studies have described the direct linking between PPARγand the death receptor signaling in the pathology of liver fibrosis.Sung et al. reported that TNF-α inhibited PPARγ activity at post-translational level in HSCs by disrupting PPARγ-PPRE binding andERK1/2-mediated phosphorylation of PPARγ at Ser82 but not viathe NF-κB pathway [135]. These results may help account at leastin part for the dramatically diminished PPARγ expression in liverfibrogenesis, where inflammation is persistent with excessive pro-duction of TNF-α [136]. The death ligands are likely to be externalfactors promoting PPARγ depletion in activated HSCs in additionto the intracellular genetic alterations. Furthermore, Wang et al.recently demonstrated that PPARγ interaction with death receptor(especially DR5) pathway was predominant in the apoptosis trig-gered by C/EBP-α in HSCs, underlying the in vivo observation thattransfection of C/EBP-α gene ameliorated CCl4-induced hepaticfibrosis [137]. The data in this study provided clear evidence thatPPARγ modulates the extrinsic pathway of apoptosis in HSCs. Itwill also be important to perform more studies with in vivo modelsto define the importance of these molecular associations in liverfibrogenesis.

5.2. The intrinsic pathway

The intrinsic pathway of apoptosis, known as mitochondrial path-way, is initiated by the intracellular stimuli and primarily mediatedby the Bcl-2 family proteins that act as sensors to integrate deathand survival signals at the level of mitochondria keeping the balancebetween proapoptotic (i.e., Bid, Bad, Bax) and antiapoptotic (Bcl-2and Bcl-xL) members of the family. The intracellular apoptotic stressleads to mitochondrial outer membrane permeabilization and subse-quently cytochrome C release, a nearly universal event in apoptosis,and triggers a final caspase-dependent apoptosis cascade (mainlyinvolving caspase-9, -3 and -7 in sequence) culminating in cellularfragmentation. Meanwhile, endogenous cellular inhibitors of apo-ptosis proteins normally inhibiting accidentally activated caspasesare neutralized [138]. In the context of liver fibrosis, rat HSCs canundergo apoptosis via Bcl-2 and caspase signaling pathway, andmicroRNA-15b and -16 are identified to be essentially involved bygene ontology analysis [139]. However, activated human HSCs intheir myofibroblast-like phenotype to undergo caspase-dependentapoptosis are markedly resistant to most proapoptotic stimuli ofpotential pathophysiological or therapeutic relevance, possiblydue to Bcl-2 overexpression [140]. These findings not only highlightthe mechanistic disparities between rodents and humans, but ofclinical significance, imply that thefibrosis reversal observed in humansmay not be entirely dependent on HSC apoptosis and needs long-duration therapy.

Molecular interactions of PPARγ with the intrinsic pathway of ap-optosis have been delineated. PPARγ was found to mediate mito-chondrial apoptotic pathway in liver associated with transcriptionalregulation of proapoptotic factor Cidea (mitochondrial cell death-inducing DNA fragmentation factor α-like effector A), a novel targetgene of PPARγ [141]. PPARγ also induced apoptosis via upregulatingcathepsin L expression in human monocyte-derived macrophages,which further promoted Bcl-2 degradation without affecting Baxprotein level [142]. Activation of PPARγ by its natural or syntheticligands has also been shown to induce apoptosis in many types ofcells including HSCs. Our data demonstrated that the natural PPARγligand curcumin was a potent apoptosis-inducing agent in activatedHSCs in vitro through increasing Bax abundance and reducing Bcl-2level, and stimulating caspase-3 activity [50]. Synthetic ligand trogli-tazone induced apoptosis of liver cancer cells in a caspase-3-dependent manner via inhibiting expression of survivin, anapoptosis-inhibiting factor, and driving it to translocate from nucleus

to cytoplasm, whereas Bax expression was not affected [143]. Theproapoptotic effects of PPARγ agonists via mitochondrial pathwaywere also recaptured in rat primary adipocytes, involving the inhibitionof AKT-1 and Bcl-2, which decreased Bad phosphorylation and inducedcytochrome C release and caspase-3 activation [144]. These findingssuggest that activation of the intrinsic pathway may be an impor-tant event in apoptosis induced by ligand activation of PPARγ.However, PPARγ-independent mechanism was also observed in Bcl-2-mediated apoptosis induced by PPARγ ligands in prostate cancer cells[145].

Although it seems that PPARγ and its ligands are proapoptotic viastimulating mitochondrial apoptotic pathway, the conversed effectsalso existed in some other cell types in various pathological contexts,such as hepatocytes in hemorrhagic shock [146], hippocampalneurons in oxidative stress [147], and cardiomyocytes in ischemiccardiac disease [148]. Under these situations, PPARγ was shown toupregulate the Bcl-2 anti-apoptotic protein and thereby protect thecells against apoptosis. Taken together, the molecular interpretationsfor PPARγ interaction with the intrinsic pathway of apoptosis have noexclusive conclusions yet, but they indeed provide novel insights intothe apoptotic mechanisms in liver fibrogenesis. Their implications fortargeted apoptosis in HSCs and for hepatocyte apoptosis preventionin fibrosis therapy remain to be defined.

6. PPARγ modulation of cellular senescence

Cellular senescence is defined as a process in which cells lose theirability to proliferate. Senescent cells are irreversibly arrested at theG1 phase of cell cycle without responses to external stimuli but main-tain their metabolic activities [149]. Senescence is associated with aset of specific alterations in gene expression pattern, exhibiting sever-al characteristics that distinguish senescent cells from quiescent ones,including shortened telomeres, upregulated activity of senescence-associated β-galactosidase (SA-β-gal), and elevated expression ofp16INK4α and p21WAF1/CIP [150], of which p16INK4α is a key biomarkerof aging in vivo [151], and its accumulation can trigger the onset ofcellular senescence [152].

Cellular senescence is involved in pathology of various liverdiseases. Hepatocyte-specific senescence due to telomere shorteningcorrelated with liver cirrhosis in both experimental [153] andhuman contexts [154]. Telomere shortening also induced hepatocytesenescence in the HCV-infected liver via elevated cell-cycle turnover,and oxidative stress accelerated this process especially in theadvanced stage of fibrosis [155]. The tumor suppressor p53 is anothercritical performer in cellular senescence program. Reactivation ofendogenous p53 in p53-deficient hepatocellular carcinoma led tocomplete regression of hepatocellular carcinoma [156, 157].Furthermore, senescent human HSCs showed less fibrogenic pheno-type and expressed decreased ECM proteins [158]. Senescence ofactivated HSCs also contributed to the clearance of profibrogenicHSCs in the fibrotic liver, and p53 and nature killer cells played acritical role [159]. These observations advance the understandingtoward fibrosis reversal complimentary to the apoptotic mecha-nisms, but how HSC senescence is initiated, and how relevantthese findings in rodents is to liver fibrosis pathogenesis in humansremain to be defined. More recently, there has been clinicalevidence that cellular senescence in the liver of children with end-stage liver disease was associated with damage rather thancorresponding to an age-dependent phenomenon [160]. Furtherstudies are needed to assess the hypothesis that these senescencemarkers correlate with liver disease progression.

Several recent studies have described the cross-regulation ofPPARγ system in cellular senescence. Gan et al. reported that PPARγactivation enhanced SA-β-gal and p16INK4α expression, induced G1arrest and delayed cell growth in human diploid fibroblasts, andthereby accelerated cellular senescence. PPARγ bound to the p16

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promoter and induced its transcription, but phosphorylation ofPPARγ decreased with increased cell passage [161]. A later in vitroinvestigation demonstrated a negative feedback and self-regulationloop, in which ligand-activated PPARγ interacted with human SIRT1(silent information regulator type 1) and inhibited its activity, forregulation of senescence in human embryonic lung diploid fibro-blasts, suggesting a new post-translational modification that may af-fect cellular senescence. And acetylation of PPARγ was shown toincrease with increasing cell passage number in this study [162].Recently, a knockout study defined the role of senescence markerprotein 30 (SMP30), which is highly expressed in liver and functionsto protect hepatocytes from apoptosis by promoting vitamin Csynthesis, in liver fibrogenesis. Neither quiescent HSCs nor activatedones expressed SMP30, but SMP30 depletion upregulated PPARγexpression and attenuated liver fibrosis, implying that PPARγ antago-nism to SMP30 could inhibit hepatocyte senescence for antifibroticpotential [163]. Consistent with this, deficiency of growth hormonereceptor/binding protein led to significant PPARγ upregulation inliver and showed extended life-spans inmice, indicating the potentialof an antiaging role for PPARγ [164]. Altogether, current data actuallycannot draw a definite conclusion for PPARγ modulation of cellularsenescence, which is presumably dependent on cell types or patholog-ical circumstances. Since HSC senescence has been identified in fibro-genesis, there is a special need to elucidate how PPARγ interferes withthe senescence signaling in activated HSCs with the aim of identifyingmechanisms that can be selectively targeted to promote HSC clearancewhile leaving its functions intact in other liver cells.

7. Implications and future directions

Continuous unraveling of PPARγ biology and molecular basisunderlying liver fibrogenesis has established the pivotal role forPPARγ system in cross-regulation of the signaling transductionsand cellular events implicated in liver fibrogenic mechanisms. Wehere provide a general mode for PPARγ regulation of signal pathways

Fig. 2. This diagram summarizes the PPARγ regulation of some key signal transduction patdiate the activation of intracellular signaling pathways through binding to specific receptorTGF-β and leptin are profibrogenic, whereas pathways transmitted by HGF and adiponectthese cascades in the context of liver fibrogenesis, and shows antifibrotic potential. Blue arDashed lines indicate certain downstream cascades performed by some cytokines and tran

mediated by several growth factors and adipokines discussed in theabove sections (Fig. 2).These novel insights portray a new paradigmof liver fibrogenesis. There are already efforts underway to translatethese discoveries into potential therapies. PPARγ gene therapy andthiazolidinedione PPARγ ligands have indeed shown therapeuticbenefits for liver fibrosis treatment in both laboratory contexts andclinical patients with chronic liver diseases [31, 165].

We need more molecular investigations into the interplay ofPPARγ and new signaling events implicated in liver fibrosis tosupport the rationale for PPARγ-targeted antifibrotic therapy. Liverfibrosis has no longer been considered to be a single and irreversibledisease, but rather a broader category subdivided by progressivestatus, reversibility, and complication with metabolism syndromesuch as hyperinsulinemia [166]. The liver is an insulin sensitiveorgan that plays a critical role in regulating glucose homeostasis.Elevated insulin signaling stimulates HSC activation by inducingmitogenesis and collagen synthesis [167]. Given that PPARγ is also acritical regulator in metabolic syndrome, it is interesting to speculatethat PPARγ has interactions with insulin pathway in HSCs, which mayaffect liver fibrogenic mechanisms. Furthermore, the liver has beenidentified as an important immunoregulatory organ and innateimmune and inflammatory systems are critically involved in liver pa-thology. Intact Toll-like receptor (TLR)-4 signaling triggered by lipo-polysaccharide has been identified in HSCs and mediates keyresponses including inflammatory phenotype, fibrogenesis and anti-apoptotic properties [168]. Further clarification of the PPARγ interac-tions with TLR signaling in HSCs and other liver cells can uncovernovel mechanisms of fibrogenesis and facilitate the development oftherapeutic strategies.

As we have discussed, the experimental results on PPARγ cross-regulation of signaling events provide stimulatory impulses for thedevelopment of effective antifibrotics targeting signal transduction.However, these signaling pathways exist in numerous cell types inthe body and have impacts on a considerable number of genes. Forthis reason, it may be necessary to develop agents that selectively

hways implicated in liver fibrogenesis. Several growth factors and adipokines that me-s are involved in the dynamic process of fibrogenesis. Pathways transmitted by PDGF,in are antifibrogenic. PPARγ as a pivotal molecular has different regulatory effects onrows indicate positive regulation, whereas red connectors denote negative regulation.scriptional factors transmitting the signals to the nucleus.

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regulate the interplay of PPARγ and signalings specific in certain celltypes such as HSCs in order to prevent or at least limit unwantedside effects. Moreover, with respect to cellular senescence, PPARγseems to protect hepatocytes form senescence [163], which couldbe beneficial for fibrosis resolution. How precisely PPARγ modulatessenescence signaling in HSCs would be another potential area of re-search for the future. Noteworthy, many appreciated discoveries dis-cussed in this review are obtained from studies in vitro, and have notyet been explored in animals or humans. We thus should also dedi-cate more research to define these cellular and molecular mecha-nisms in vivo for further validating the potential drug targets andsearching for therapeutic approaches. Basic and preclinical studiesinto PPARγ-mediated mechanisms in liver fibrogenesis are clearly en-couraging and it is an intriguing task to investigate if these novel mo-lecular insights will allow the beneficial therapies for the millions ofpatients suffering from chronic liver diseases worldwide.

Conflict of interest

The authors disclose no conflicts.

Author contributions

Feng Zhang was the major drafter of the manuscript; Yin Luprovided essential assistance in data analysis, and administrativeand technical support; and Shizhong Zheng was responsible for thestudy concept and critical revision of the manuscript for importantintellectual content.

Acknowledgments

The financial supportwas fromNational Natural Science Foundationof China (30873424), Jiangsu Natural Science Foundation (BK2008456),Project for Supporting Jiangsu Provincial Talents in Six Fields (2009-B-010), Doctoral Discipline Foundation of Ministry of Education of China(20103237110010), Open Program of Jiangsu Key Laboratory of Acu-puncture &Medicine (KJA200801), and a project funded by the PriorityAcademic Program Development of Jiangsu Higher Education Institu-tions (ysxk-2010). We are grateful to Wenhui Qian for helpful sugges-tions and material collection.

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