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

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-gamma (PPAR gamma), 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 PPAR gamma inhibits HSC collagen production and modulates HSC adipogenic phenotype at transcriptional and epigenetic levels. These molecular insights indicate PPAR gamma as a promising drug target for antifibrotic chemotherapy. Intensive animal studies have demonstrated that stimulation of PPAR gamma regulatory system through gene therapy approaches and PPAR gamma 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 PPAR gamma regulation of HSC pathophysiology and then focuses on the animal investigations and clinical trials of various therapeutic modalities targeting PPAR gamma for hepatic fibrosis.