Theranostics 2014; 4(2):215-228. doi:10.7150/thno.7868

Research Paper

Quantitative Liver-Specific Protein Fingerprint in Blood: A Signature for Hepatotoxicity

Zhiyuan Hu1,2,3✉*, Christopher Lausted2✉*, Hyuntae Yoo2,4, Xiaowei Yan2, Amy Brightman2, Jiankui Chen5, Weizhi Wang1, Xiangli Bu1, Leroy Hood2

1. National Center for NanoScience and Technology, 11 BeiYiTiao, ZhongGuanCun, Beijing, 100190, China.
2. Institute for Systems Biology, 401 Terry Avenue N, Seattle, Washington 98109, USA.
3. State Key Laboratory of Proteomics, Beijing Proteomics Research Center, Beijing 100850, China.
4. University of Texas at Dallas, Department of Molecular and Cell Biology, FO 31, 800 West Campbell Road, Richardson, Texas 75080, USA.
5. Beijing 307 Hospital, Department of Laboratory Medicine, Beijing 100071, China.
* The first two authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See for full terms and conditions.
Hu Z, Lausted C, Yoo H, Yan X, Brightman A, Chen J, Wang W, Bu X, Hood L. Quantitative Liver-Specific Protein Fingerprint in Blood: A Signature for Hepatotoxicity. Theranostics 2014; 4(2):215-228. doi:10.7150/thno.7868. Available from

File import instruction


We discuss here a new approach to detecting hepatotoxicity by employing concentration changes of liver-specific blood proteins during disease progression. These proteins are capable of assessing the behaviors of their cognate liver biological networks for toxicity or disease perturbations. Blood biomarkers are highly desirable diagnostics as blood is easily accessible and baths virtually all organs. Fifteen liver-specific blood proteins were identified as markers of acetaminophen (APAP)-induced hepatotoxicity using three proteomic technologies: label-free antibody microarrays, quantitative immunoblotting, and targeted iTRAQ mass spectrometry. Liver-specific blood proteins produced a toxicity signature of eleven elevated and four attenuated blood protein levels. These blood protein perturbations begin to provide a systems view of key mechanistic features of APAP-induced liver injury relating to glutathione and S-adenosyl-L-methionine (SAMe) depletion, mitochondrial dysfunction, and liver responses to the stress. Two markers, elevated membrane-bound catechol-O-methyltransferase (MB-COMT) and attenuated retinol binding protein 4 (RBP4), report hepatic injury significantly earlier than the current gold standard liver biomarker, alanine transaminase (ALT). These biomarkers were perturbed prior to onset of irreversible liver injury. Ideal markers should be applicable for both rodent model studies and human clinical trials. Five of these mouse liver-specific blood markers had human orthologs that were also found to be responsive to human hepatotoxicity. This panel of liver-specific proteins has the potential to effectively identify the early toxicity onset, the nature and extent of liver injury and report on some of the APAP-perturbed liver networks.

Keywords: liver injury, toxicity, biomarker, RBP4, COMT, CPS1, BHMT.