Glycocapture-Assisted Global Quantitative Proteomics (gagQP) Reveals Multiorgan Responses in Serum Toxicoproteome

Abstract

Blood is an ideal window for viewing our health and disease status. Because blood circulates throughout the entire body and carries secreted, shed, and excreted signature proteins from every organ and tissue type, it is thus possible to use the blood proteome to achieve a comprehensive assessment of multiple-organ physiology and pathology. To date, the blood proteome has been frequently examined for diseases of individual organs; studies on compound insults impacting multiple organs are, however, elusive. We believe that a characterization of peripheral blood for organ-specific proteins affords a powerful strategy to allow early detection, staging, and monitoring of diseases and their treatments at a whole-body level. In this paper we test this hypothesis by examining a mouse model of acetaminophen (APAP)-induced hepatic and extra-hepatic toxicity. We used a glycocapture-assisted global quantitative proteomics (gagQP) approach to study serum proteins and validated our results using Western blot. We discovered in mouse sera both hepatic and extra-hepatic organ-specific proteins. From our validation, it was determined that selected organ-specific proteins had changed their blood concentration during the course of toxicity development and recovery. Interestingly, the peak responding time of proteins specific to different organs varied in a time-course study. The collected molecular information shed light on a complex, dynamic, yet interweaving, multiorgan-enrolled APAP toxicity. The developed technique as well as the identified protein markers is translational to human studies. We hope our work can broaden the utility of blood proteomics in diagnosis and research of the whole-body response to pathogenic cues.

Membrane gene ontology bias in sequencing and microarray obtained by housekeeping-gene analysis

“…It is also well known that membrane proteins are lowly abundant, for proteomic analysis in which no amplification of protein quantity is possible, membrane proteins are extremely difficult to be detected and always require sophisticated enrichment and/or sensitive instruments for analysis [62]. Therefore, our current study as well as previous results supported the discovery of Young however, the better understanding of their limitations will encourage future improvement for accurate interrogation of biological systems.…”

Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury

“…ICAT labeling in combination with LC-MS/MS was employed to measure mouse whole liver proteome changes after APAP treatment [32]. In a very recent study, Sun et al [33] examined the blood proteome in a mouse model of APAP-induced hepatotoxicity (a single dose administered through i.p. injection) using a quantative LC-MS/MS approach based on amine-specific isotope labeling.…”

“…In a very recent study, Sun et al. examined the blood proteome in a mouse model of APAP‐induced hepatotoxicity (a single dose administered through i.p. injection) using a quantative LC‐MS/MS approach based on amine‐specific isotope labeling.…”

Systems Biology and P4 Medicine: Past, Present, and Future

“…Additionally, membrane-cleaved proteins as well as secreted proteins will provide fundamental insights. In a mouse study that we conducted on the toxicity of acetaminophen, a classical hepatotoxic substance, perturbations were found in seven other organs as well 13. This shows the power of organ-specific markers that enable us to see how organs actually communicate with each other as a network.…”