Proteomic Signature of Acute Liver Failure: From Discovery and Verification in a Pig Model to Confirmation in Humans.
Acute liver failure (ALF) is a fatal condition hallmarked by rapid development. The present study aimed to describe the dynamic alterations of serum proteins associated with ALF development, and to seek for novel biomarkers of ALF. Miniature pigs (n= 38) were employed to establish ALF models by infusing d-galactosamine (GALN, 1.3 g/kg). A total of 1310 serum proteins were compared in pooled serum samples (n= 10) before and 36 h after GALN administration through label-free quantitation (LFQ) based shotgun proteomics. Functional analysis suggested a significant enrichment of ALF-related proteins involved in energy metabolism. Temporal changes of 20 energy metabolism related proteins were investigated in individual pigs (n= 8) via parallel reaction monitoring (PRM) based targeted proteomics. In addition, mitochondrion degeneration and gene expression alteration of aerobic metabolism genes were confirmed in GALN-insulted pig liver. In clinical validation study enrolled 34 ALF patients and 40 healthy controls, fructose-1,6-bisphosphatase 1 (FBP1) showed a prognostic value for short-term survival (30 days) equal to that of the Model of End-stage Liver Disease score (ROC-AUC = 0.778). Survival analysis suggested significantly higher death-related hazard in ALF patients with higher FBP1 levels (>16.89 μg/dL) than in those with lower FBP1 levels (p= 0.002). Additionally, serum retinol binding protein 4 (RBP4) level was found decreased prior to ALT elevation in GALN-insulted pig model. We also confirmed that serum level of RBP4 is significantly lower in ALF patients (p< 0.001) as compared with healthy controls. In summary, this translational study, displayed by multistaged proteomics techniques, unveiled underlying functional changes related to the development of ALF and facilitated the discovery of novel ALF markers.
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Jie
J
Wang
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Zeyu
0000-0003-0218-2277
Z
Sun
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Jing
J
Jiang
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Daxian
D
Wu
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Xiaoli
X
Liu
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Zhongyang
Z
Xie
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Ermei
E
Chen
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Danhua
D
Zhu
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Chao
C
Ye
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Xiaoqian
X
Zhang
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Wenqian
W
Chen
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China.
Hongcui
H
Cao
From the ‡State Key Laboratory for Diagnosis and Treatment of Infectious Diseases; Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China ljli@zju.edu.cn.
Lanjuan
L
Li
D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D004265:DNA Helicases / Q000097:blood*; D004268:DNA-Binding Proteins / Q000097:blood*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005260:Female; D005688:Galactosamine / Q000009:adverse effects; D005786:Gene Expression Regulation; D006801:Humans; D017114:Liver Failure, Acute / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D011379:Prognosis; D040901:Proteomics / Q000379:methods*; D016601:RNA-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*; D016019:Survival Analysis; D013552:Swine; D013556:Swine, Miniature
D015415:Biomarkers; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; C101326:RBP4 protein, human; D016601:RNA-Binding Proteins; D054839:Retinol-Binding Proteins, Plasma; D005688:Galactosamine; D004265:DNA Helicases