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

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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.

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Acknowledgments

We thank the financial support from the Open Project Program of National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine (2011ZYX4-008), Doctoral Discipline Foundation of Ministry of Education of China (20103237110010), National Natural Science Foundation of China (30873424), Jiangsu Natural Science Foundation (BK2008456), Project for Supporting Jiangsu Provincial Talents in Six Fields (2009112), Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (ysxk-2010), and “Eleven-Five” National Science and Technology Supporting Program (2008BAI51B02). We are grateful to Dr. Shile Huang, Louisiana State University Health Sciences Center, USA, for his critical reading and reversion of the manuscript.

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  1. Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, 282 Hanzhong Road, Nanjing, 210029, Jiangsu, China

    Feng Zhang, Desong Kong, Yin Lu & Shizhong Zheng

  2. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210046, China

    Yin Lu & Shizhong Zheng

  3. National First-Class Key Discipline for Traditional Chinese Medicine of Nanjing University of Chinese Medicine, Nanjing, 210046, China

    Yin Lu & Shizhong Zheng

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Correspondence to Shizhong Zheng.

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Zhang, F., Kong, D., Lu, Y. et al. Peroxisome proliferator-activated receptor-γ as a therapeutic target for hepatic fibrosis: from bench to bedside. Cell. Mol. Life Sci. 70, 259–276 (2013). https://doi.org/10.1007/s00018-012-1046-x

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