Fibrosis, or the accumulation of extracellular matrix, causes loss of organ function and is a common feature of many chronic diseases. To interrogate the core molecular pathways of fibrosis, we cross-examined human primary cells from various tissues treated with TGFβ. Transcriptome analyses revealed that in addition to the known TGFβ signature, top-regulated cluster of genes are involved in fatty acid metabolism. To further evaluate this observation in vivo, we characterized a renal fibrosis model through unilateral ureteral obstruction (UUO) in mice. TGFβ signaling was greatly augmented in UUO kidneys and preventive treatment with an anti-TGFβ antibody resulted in significant reduction of fibrosis. Transcriptome analysis also identified fatty acid metabolism as one of the top dysregulated pathways in UUO kidneys, which was further supported by a substantial accumulation of acylcarnitines. Additional rodent models of liver fibrosis revealed a similar metabolic signature upon fibrosis induction. Lastly, a compound library phenotypic screen for suppressers of fibrosis identified AMPK and PPAR activators. As a proof of concept, we demonstrated that pharmacological treatment of telmisartan, an angiotensin receptor and PPARγ dual-agent, significantly reduced fibrosis in UUO kidneys, suggesting that metabolic defect is integral to TGFβ signaling and fibrosis. Altogether, our work has revealed a common node of metabolic signature underlying fibrosis that could represent a promising therapeutic target for multiple fibrotic diseases.
Zhang, Ji and Muise, Eric S. and Kutchukian, Peter S. and Costet, Philippe and Zhu, Yonghua and Kan, Yanqing and Zhou, Haihong and Shah, Vinit and Huang, Yongcheng and Akiyama, Taro E. and Shen, Xiao-Lan and Cai, Tian-Quan and Shah, Kashmira and Zycband, Emanuel and Yi, Lan and Tian, Ye and Chen, Ying and Imbriglio, Jason and Smith, Elizabeth and Devito, Kristine and Conway, James and Ma, Li-Jun and Hoek, Maarten and Peier, Andrea M. and McLaren, David G. and Previs, Stephen F. and Pinto, Shirly, Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis (2018). Available at SSRN: https://ssrn.com/abstract=3209457 or http://dx.doi.org/10.2139/ssrn.3209457
This version of the paper has not been formally peer reviewed.
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