title: Chronological Profiling of Plasma Native Peptides after Hepatectomy in Pigs: Toward the Discovery of Human Biomarkers for Liver Regeneration.
abstract: Liver regeneration after partial hepatectomy (PHx) is a time-dependent process, which is tightly regulated by multiple signaling cascades. Failure of this complex process leads to posthepatectomy liver failure (PHLF), which is associated with a high rate of mortality. Thus, it is extremely important to establish a useful biomarker of liver regeneration to help prevent PHLF. Here, we hypothesized that alterations in the plasma peptide profile may predict liver regeneration following PHx and hence we set up a diagnostic platform for monitoring posthepatectomy outcome. We chronologically analyzed plasma peptidomic profiles of 5 partially hepatectomized microminipigs using the ClinProtTM system, which consists of magnetic beads and MALDI-TOF/TOF MS. We identified endogenous circulating peptides specific to each phase of the postoperative course after PHx in pigs. Notably, peptide fragments of histones were detected immediately after PHx; the presence of these fragments may trigger liver regeneration in the very acute phase after PHx. An N-terminal fragment of hemoglobin subunit α (3627 m/z) was detected as an acute-phase-specific peptide. In the recovery phase, the short N-terminal fragments of albumin (3028, 3042 m/z) were decreased, whereas the long N-terminal fragment of the protein (8926 m/z) was increased. To further validate and extract phase-specific biomarkers using plasma peptidome after PHx, plasma specimens of 4 patients who underwent PHx were analyzed using the same method as we applied to pigs. It revealed that there was also phase-specificity in peptide profiles, one of which was represented by a fragment of complement C4b (2378 m/z). The strategy described herein is highly efficient for the identification and characterization of peptide biomarkers of liver regeneration in a swine PHx model. This strategy is feasible for application to human biomarker studies and will yield clues for understanding liver regeneration in human clinical trials.
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Iguchi
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Etsuro
authors.initials: E
authors.lastname: Hatano
authors.affiliation: Bruker Daltonics K. K., Yokohama, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nirasawa
authors.affiliation: Bruker Daltonics K. K., Yokohama, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Iwasaki
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Gen
authors.initials: G
authors.lastname: Yamamoto
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Yamanaka
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Okamoto
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kasai
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Naohiko
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fuji
authors.affiliation: Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Department of Life and Medical Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
authors.forename: Nobuto
authors.initials: N
authors.lastname: Kakuda
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Seo
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Taura
authors.affiliation: Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Tashiro
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.affiliation: Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan.|Department of Life and Medical Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
authors.forename: Masaya
authors.identifier: 0000-0001-8731-9919
authors.initials: M
authors.lastname: Ikegawa
mesh_terms: D000818:Animals; D015415:Biomarkers; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006498:Hepatectomy; D006801:Humans; D008115:Liver Regeneration; D010455:Peptides / Q000097:blood*; D012372:ROC Curve; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013552:Swine; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D010455:Peptides