Thyroid hormone signaling in hepatic fibrogenesis

• Applicant: Dr. Paul Manka
• Subject Area: Gastroenterology
• Term: from 2015 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 276096991

Fibrosis is a pathological feature of most chronic inflammatory diseases. It is defined by the accumulation of excess extracellular matrix components. If highly progressive, the fibrotic process eventually leads to organ malfunction and death. Ultimately, in the liver fibrosis leads to cirrhosis and increases the risk of developing liver cancer. Treatment strategies which specifically target the pathogenesis of fibrosis are very few and not approved. Chronic liver injury triggers cell repair response and liver fibrosis occurs when repair becomes deregulated. The functional basis for fibrosis and cirrhosis during chronic liver injury is activation of non-parenchymal cells, such as hepatic stellate cells. Thyroid hormone (triiodothyronine, T3 and L-thyroxine, T4) signaling is critical for tissue and organ development, growth, differentiation and metabolism (including lipid and cholesterol handling) The two major thyroid receptor isoforms, thyroid hormone receptor alpha 1 and beta 1 (TRalpha and TRbeta) have tissue-specific distribution. Preliminary data show that TRalpha and TRbeta are expressed in hepatic stellate cells, and treatment with transforming growth factor beta (TGF-beta), a profibrogenic cytokine, causes downregulation of TRalpha and TRbeta in hepatic stellate cells. Conversely, treatment with T3 abrogates the activation of hepatic stellate cells. Our project aims to evaluate the role of thyroid hormone signaling in hepatic fibrogenesis. Specifically, we will study if, and how thyroid hormones modulate hepatic stellate cell responses in cell culture systems. Further it is aim to determine if perturbations in thyroid hormone signaling occur in patients with chronic liver diseases. Following studies will involve the use of thyroid hormone receptor-specific knockout mice, to confirm the physiological relevance of thyroid hormone signaling in liver disease. Impact of liver fibrosis in society - costs, and the lack of approved therapies to treat liver fibrosis, hence the need to understand mechanisms and identify novel therapeutic targets. The results of this proposal may shed new insights into the mechanisms which regulate hepatic fibrogenesis, and may translate into new therapeutic strategies.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Dr. Wing-Kin Syn