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Molecular Profiling Reveals a Common Metabolic Signature of Tissue Fibrosis

53 Pages Posted: 10 Jul 2018 Publication Status: Review Complete

See all articles by Ji Zhang

Ji Zhang

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Eric S. Muise

Merck & Co., Inc. - Department of Genetics and Pharmacogenomic (GpGx)

Peter S. Kutchukian

Merck & Co., Inc. - Department of Chemistry

Philippe Costet

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Yonghua Zhu

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Yanqing Kan

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Haihong Zhou

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Vinit Shah

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Yongcheng Huang

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Taro E. Akiyama

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Xiao-Lan Shen

Merck & Co., Inc. - Department of Safety Assessment and Laboratory Animals Resources (SALAR)

Tian-Quan Cai

Merck & Co., Inc. - Department of Pharmacology

Kashmira Shah

Merck & Co., Inc. - Department of Pharmacology

Emanuel Zycband

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Lan Yi

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Ye Tian

Merck & Co., Inc. - Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM)

Ying Chen

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Jason Imbriglio

Merck & Co., Inc. - Department of Chemistry

Elizabeth Smith

Merck & Co., Inc. - Department of Pharmacology

Kristine Devito

Merck & Co., Inc. - Department of Pharmacology

James Conway

Merck & Co., Inc. - Department of Genetics and Pharmacogenomic (GpGx)

Li-Jun Ma

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Maarten Hoek

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Andrea M. Peier

Merck & Co., Inc. - Department of Pharmacology

David G. McLaren

Merck & Co., Inc. - Department of Chemistry

Stephen F. Previs

Merck & Co., Inc. - Department of Cardiometabolic Diseases

Shirly Pinto

Merck & Co., Inc. - Department of Cardiometabolic Diseases

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Abstract

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.

Suggested Citation

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.

Ji Zhang (Contact Author)

Merck & Co., Inc. - Department of Cardiometabolic Diseases ( email )

770 Sumneytown Pike
West Point, PA 19486
United States

Eric S. Muise

Merck & Co., Inc. - Department of Genetics and Pharmacogenomic (GpGx) ( email )

770 Sumneytown Pike
West Point, PA 19486
United States

Peter S. Kutchukian

Merck & Co., Inc. - Department of Chemistry

770 Sumneytown Pike
West Point, PA 19486
United States

Philippe Costet

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Yonghua Zhu

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Yanqing Kan

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Haihong Zhou

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Vinit Shah

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Yongcheng Huang

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Taro E. Akiyama

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Xiao-Lan Shen

Merck & Co., Inc. - Department of Safety Assessment and Laboratory Animals Resources (SALAR)

770 Sumneytown Pike
West Point, PA 19486
United States

Tian-Quan Cai

Merck & Co., Inc. - Department of Pharmacology

770 Sumneytown Pike
West Point, PA 19486
United States

Kashmira Shah

Merck & Co., Inc. - Department of Pharmacology

770 Sumneytown Pike
West Point, PA 19486
United States

Emanuel Zycband

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Lan Yi

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Ye Tian

Merck & Co., Inc. - Department of Pharmacokinetics, Pharmacodynamics and Drug Metabolism (PPDM)

770 Sumneytown Pike
West Point, PA 19486
United States

Ying Chen

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Jason Imbriglio

Merck & Co., Inc. - Department of Chemistry

770 Sumneytown Pike
West Point, PA 19486
United States

Elizabeth Smith

Merck & Co., Inc. - Department of Pharmacology

770 Sumneytown Pike
West Point, PA 19486
United States

Kristine Devito

Merck & Co., Inc. - Department of Pharmacology

770 Sumneytown Pike
West Point, PA 19486
United States

James Conway

Merck & Co., Inc. - Department of Genetics and Pharmacogenomic (GpGx)

770 Sumneytown Pike
West Point, PA 19486
United States

Li-Jun Ma

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Maarten Hoek

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Andrea M. Peier

Merck & Co., Inc. - Department of Pharmacology

770 Sumneytown Pike
West Point, PA 19486
United States

David G. McLaren

Merck & Co., Inc. - Department of Chemistry

770 Sumneytown Pike
West Point, PA 19486
United States

Stephen F. Previs

Merck & Co., Inc. - Department of Cardiometabolic Diseases

770 Sumneytown Pike
West Point, PA 19486
United States

Shirly Pinto

Merck & Co., Inc. - Department of Cardiometabolic Diseases ( email )

770 Sumneytown Pike
West Point, PA 19486
United States

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