Peroxisome proliferator-activated receptor-γ as a therapeutic target for hepatic fibrosis: from bench to bedside

Abstract

Hepatic fibrosis is a dynamic chronic liver disease occurring as a consequence of wound-healing responses to various hepatic injuries. This disorder is one of primary predictors for liver-associated morbidity and mortality worldwide. To date, no pharmacological agent has been approved for hepatic fibrosis or could be recommended for routine use in clinical context. Cellular and molecular understanding of hepatic fibrosis has revealed that peroxisome proliferator-activated receptor-γ (PPARγ), the functioning receptor for antidiabetic thiazolidinediones, plays a pivotal role in the pathobiology of hepatic stellate cells (HSCs), whose activation is the central event in the pathogenesis of hepatic fibrosis. Activation of PPARγ inhibits HSC collagen production and modulates HSC adipogenic phenotype at transcriptional and epigenetic levels. These molecular insights indicate PPARγ as a promising drug target for antifibrotic chemotherapy. Intensive animal studies have demonstrated that stimulation of PPARγ regulatory system through gene therapy approaches and PPARγ ligands has therapeutic promise for hepatic fibrosis induced by a variety of etiologies. At the same time, thiazolidinedione agents have been investigated for their clinical benefits primarily in patients with nonalcoholic steatohepatitis, a common metabolic liver disorder with high potential to progress to fibrosis and liver-related death. Although some studies have shown initial promise, none has established long-term efficacy in well-controlled randomized clinical trials. This comprehensive review covers the 10-year discoveries of the molecular basis for PPARγ regulation of HSC pathophysiology and then focuses on the animal investigations and clinical trials of various therapeutic modalities targeting PPARγ for hepatic fibrosis.

Fig. 1

Mechanisms of PPARγ regulation of gene transcription. a The primary structure of PPARγ mainly comprises a C-terminal ligand binding domain (LBD) that harbors the ligand-dependent activation function (AF2), a zinc-finger DNA binding domain (DBD), and an N-terminal AB domain that harbors a ligand-independent function (AF1). A hinge domain links the LBD to DBD. b Ligand-dependent transactivation. In the absence of ligands, PPARγ is bound to co-repressors and prevents gene transcription. Upon binding to ligands, PPARγ undergoes conformational changes. It dissociates the co-repressors and translocates to nucleus where it recruits co-activators that have histone acetylase activity, and forms a heterodimer with RXRα. The active transcription complex then binds to the DNA response elements termed PPRE located in the promoter regions of target genes, allowing transcription activation. A number of co-activator proteins have been identified and their combinatorial usage may provide the basis for cell type- or gene-specific transcriptional responses. c Ligand-dependent transrepression. Following activated by ligands, PPARγ can interfere with the activity and function of other transcription factors such as NF-κB and AP-1, leading to disruption of their binding to target gene promoters and thereby to transcription repression. In this mechanism, PPARγ does not bind to specific DNA response elements. This transcriptional model may underlie the ability of PPARγ to negatively regulate the inflammatory responses and collagen production in hepatic fibrosis. d Ligand-independent transrepression. In the absence of ligands, PPARγ can recruit co-repressors that antagonize the effects of co-activators, leading to transcription repression of direct target genes. The most defined co-repressors are NCoR (nuclear-receptor co-repressor) and SMRT (silencing mediator of retinoic-acid and thyroid hormone receptors). In addition, protein modifications such as ubiquitination and phosphorylation have also been shown to suppress the transcription activity of PPARγ and thus play a role in the ligand-independent transrepression mechanism

Fig. 2

Representative natural and synthetic PPARγ ligands and ligand-specific PPARγ biological functions. PPARγ ligands include a wide range of chemical structures from endogenous and synthetic sources. The naturally occurring PPARγ agonist 15d-PGJ₂ is most commonly used in laboratory investigations. Thiazolidinediones including troglitazone, rosiglitazone, and pioglitazone represent an important class of therapeutic agents for type 2 diabetes. Meanwhile, nonthiazolidinedione PPARγ agonists have been increasingly developed with attractive pharmacological properties. Activation of PPARγ by ligands has been shown to produce varied transcriptional profiles and biological functions. PPARγ is originally thought to regulate adipogenesis and insulin sensitivity and thus serves as a master integrator of energy consumption and glucose homeostasis. Accumulating evidence shows that the biological outcomes of PPARγ activation are far beyond regulation of fat and glucose. PPARγ exhibits a pleiotropic role affecting a variety of pathophysiological pathways as illustrated in this schema, indicating that PPARγ may have broad implications in pharmacotherapy of diseases. The beneficial role in tissue repair and the anti-inflammatory property implicate PPARγ regulatory system in the management of hepatic fibrosis. Progress toward understanding PPARγ biology still continues