Reply
Authors: Nanping Wang, Yi Zhu
Journal: Hepatology (2008)

Nonalcoholic fatty liver disease (NAFLD) is a potentially progressive liver disease associated with hepatic insulin resistance. Although a cause-effect relationship between NAFLD and insulin resistance has not yet been confirmed, it is generally accepted that NAFLD is a hepatic component of the metabolic syndrome and an independent risk factor for the development of type 2 diabetes.1, 2 Several therapeutic approaches such as antioxidants, insulin sensitizers, and lipid-lowering agents have been tested for the treatment of NAFLD. Although a weight-reducing diet in overweight patients has proved effective, no therapeutic regime has proven effective to date.3 In our recent article "Peroxisome Proliferator-Activated Receptor-delta Induces Insulin-Induced Gene-1 and Suppresses Hepatic Lipogenesis in Obese Diabetic Mice," we demonstrated that peroxisome proliferator-activated receptor-δ (PPAR-δ) suppressed the activation of sterol regulatory element-binding protein-1 via transactivation of insulin-induced gene-1 and consequently reduced lipogenesis in cultured human hepatocytes as well as in the liver of obese diabetic mice.4 These results revealed a novel mechanism by which PPAR-δ regulates lipid metabolism. Following the publication of our article, Sharma et al. expressed their interest and concern about transforming the results from basic research into clinical practice. We generally agree with the comment from Sharma et al. that the results from basic research have to be translated into clinical practice with caution. They note that targeting a single PPAR-δ gene has a limitation, because the metabolic syndrome is an outcome of complex interaction between numerous hereditary and environmental factors and thus needs to be treated holistically. This is in line with the concept of polypill. In fact, emerging evidence shows that PPAR-δ agonists have plural effects on multiple components of the metabolic syndrome. For example, PPAR-δ agonists have been reported to increase plasma levels of high-density lipoprotein, boost fatty acid oxidation in skeletal muscle, and improve insulin sensitivity. Furthermore, PPAR-δ agonists have a suppressive effect on inflammation, which is also an important feature of hepatic steatosis. Most recently, PPAR-δ agonist has been reported to mimic and potentiate the effects of exercise in mice.5 Taken together, these results point to a potential of PPAR-δ in treating the metabolic syndrome and NAFLD. We also agree with Sharma et al. in that discrepancies may exist between the results from rodents and humans. In addition, as they suggested, using human hepatic cell lines from patients with fatty liver will be a more ideal system to further stringently examine the relevance of the mechanism to NAFLD. Notably, consistent with our results in obese diabetic mice, a recent clinical trial demonstrated that the PPAR-δ agonist significantly improved liver fat in obese men, indicating a potential benefit of PPAR-δ for NAFLD.6 We thank Sharma et al. for their comments and fully agree that clinical efficacy and safety can only be thoroughly assessed through strictly controlled clinical trials. Nanping Wang MD, PhD*, Yi Zhu MD , * Institute of Cardiovascular Science and Diabetes Center, Peking University Health Science Center, Beijing, China, Department of Physiology and Pathophysiology and Diabetes Center, Peking University Health Science Center, Beijing, China.