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

Abstract

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.

SOCS2 Balances Metabolic and Restorative Requirements during Liver Regeneration

“…We then looked at retinol-binding protein (RBP) as a measure of liver synthetic function. RBP is produced in the liver and serves as a plasma carrier protein for retinol, the lipid alcohol of vitamin A. RBP has a short half-life of 12 h, suggesting it should be a sensitive marker of decreased liver synthetic function (24). RBP levels at baseline are equivalent, but 72 h after hepatectomy were lower in Socs2-null mice compared with WT mice (Fig.…”

New potential biomarkers of acetaminophen-induced hepatotoxicity

“…It was suggested that these liver-specific blood proteins 134 might be useful in GSH and SAMe levels' assessment and therefore 135 might have prognostic value in hepatotoxicity. Hu et al [17] also 136 observed interesting changes in the concentration of membrane-137 bound catechol-O-methyltransferase (MB-COMT) in mouse 138 plasma and liver tissue after APAP intoxication. Catechol-O-139 methyltransferase (COMT) is an enzyme that catalyzes the transfer 140 of a methyl group and has two isoforms-soluble and membrane-141 bound.…”

“…130 [17] linked the decreasing SAMe with the change in the levels of 131 three enzymes involved in metabolism of SAMe (MAT1A, GNMT 132 and BHMT)-they decreased in the liver but were elevated in the 133 blood. It was suggested that these liver-specific blood proteins 134 might be useful in GSH and SAMe levels' assessment and therefore 135 might have prognostic value in hepatotoxicity.…”

“…117 2.2. Liver-specific blood proteins 118 Hu et al [17] identified five liver-specific blood proteins as 119 markers of APAP-induced hepatotoxicity in humans using 120 proteomic technologies (label-free antibody microarrays, quanti-121 tative immunoblotting, and targeted iTRAQ mass spectrometry).…”

The Importance of Standardization on Analyzing Circulating RNA

“…The discovery of disease-associated concentration changes of specific extracellular miRNA such as miR-141 for prostate cancer [5, 51, 52], miR-122 for liver related diseases [6, 53–55], miR-208 and miR-499 for cardiovascular diseases [56–59] in body fluids raised the interest of developing a circulating miRNA-based biomarker for disease diagnosis. In comparison to protein-based biomarkers, miRNA has several advantages including a much smaller repertoire, easier to develop assays with sufficient specificity, and an amplifiable detection signal.…”