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Lack of effect of delayed thiazolidinedione treatment may imply that these drugs are of limited efficacy in hepatic fibrosis, and that treatment of chronic liver disease might be successful only if the therapy were started very early
Liver tissue scarring, or fibrosis, is considered a common pathway leading to the alterations typical of cirrhosis, and delaying its progression likely results in longer patient survival and reduced need for liver transplantation. The past 15 years have witnessed a tremendous advance in our understanding of the cellular and molecular mechanisms responsible for the fibrogenic response in the liver (reviewed by Bataller and Brenner1). Damage to hepatocytes, or alterations in the biliary tree, activate mesenchymal cells that acquire a myofibroblastic phenotype, actively proliferate, produce extracellular matrix components, and secrete soluble mediators that contribute to maintenance of a chronic “wound healing” response, resulting in progressive scarring and alteration of the microvascular architecture. Activation of hepatic stellate cells (HSC) is considered a major source of myofibroblast-like cells during liver injury, together with the contribution of other myofibroblasts, such as those originating from the portal tracts.2 In spite of the clinical need for antifibrotic therapies, and a detailed knowledge of the processes of fibrogenesis in cellular and animal models, to date no drugs have been approved for the treatment of hepatic fibrosis.
A number of studies have recently suggested that antidiabetic thiazolidinediones (TZDs) or “glitazones” (from the prototype troglitazone, withdrawn from the market, and currently comprised of pioglitazone and rosiglitazone) may represent a possible novel pharmacological treatment for liver fibrosis. TZDs are employed for the treatment of insulin resistance in patients with type 2 diabetes and are selective ligands for the nuclear transcription factor peroxisome proliferator activated receptor (PPAR)γ.3 PPARs, which include PPARα, PPARβ (or -δ), and PPARγ belong to the nuclear receptor …
Competing interest: None declared.
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