Proteomics Indicates Lactate Dehydrogenase is Prognostic in Acetaminophen-induced Acute Liver Failure Patients and Reveals a Role for LKB1-AMPK Signaling
Proteomics Indicates Lactate Dehydrogenase is Prognostic in Acetaminophen-induced Acute Liver Failure Patients and Reveals a Role for LKB1-AMPK Signaling
ABSTRACT Better biomarkers to predict death early in acute liver failure (ALF) are needed. To that end, we obtained early (study day 1) and later (day 3) serum samples from transplant-free survivors (n=28) and non-survivors (n=30) of acetaminophen (APAP)-induced ALF from the NIH-sponsored Acute Liver Failure Study Group, and from control volunteers (n=10). To identify proteins that increase early in serum during ALF, we selected individuals from this cohort for whom ALT was lower on day 1 than day 3, indicating a time point before the peak of injury (n=10/group). We then performed untargeted proteomics on their day 1 samples. Out of 1,682 quantifiable proteins, 79 were elevated ≥4-fold in ALF patients vs. controls and 23 of those were further elevated ≥4-fold in non-survivors vs. survivors, indicating potential to predict death. Interestingly, the biomarker with best performance was LDH. To confirm the prognostic potential of LDH, we measured activity in all day 1 and 3 samples from all 58 ALF patients. LDH was elevated in the non-survivors vs. survivors on both days. In addition, receiver operating characteristic (ROC) curve analyses revealed that LDH alone performed similarly to the model for end-stage liver disease (MELD), while a combination of MELD and LDH outperformed either alone. Finally, Upstream Analysis of our proteomics data indicated activation of LKB1-AMPK signaling in liver regeneration after APAP overdose and we confirmed that in mice. Overall, we conclude LDH can predict death in APAP-induced ALF and that LKB1-AMPK signaling may be a promising therapeutic target to improve survival.
Vazquez Joel H.、Kennon-McGill Stefanie、Jaeschke Hartmut、Lee William M.、McGill Mitchell R.、Acute Liver Failure Study Group、Dranoff Jonathan A.、Mackintosh Samuel G.、Williams D. Keith、Byrum Stephanie D.
Dept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical SciencesDept. of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical SciencesDept. of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical CenterDiv. of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Med SchoolDept. of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences||Dept. of Environmental and Occupational Health, Fay W. Boozman College of Public Health, University of Arkansas for Medical SciencesDiv. of Gastroenterology and Hepatology, Dept. of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences Yale University School of MedicineDept. of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical SciencesDept. of Biostatistics, College of Medicine, University of Arkansas for Medical SciencesDept. of Biochemistry and Molecular Biology, College of Medicine, University of Arkansas for Medical Sciences
基础医学生物科学研究方法、生物科学研究技术生物化学
Drug-induced liver injuryacute liver injuryliver regenerationbiomarkers
Vazquez Joel H.,Kennon-McGill Stefanie,Jaeschke Hartmut,Lee William M.,McGill Mitchell R.,Acute Liver Failure Study Group,Dranoff Jonathan A.,Mackintosh Samuel G.,Williams D. Keith,Byrum Stephanie D..Proteomics Indicates Lactate Dehydrogenase is Prognostic in Acetaminophen-induced Acute Liver Failure Patients and Reveals a Role for LKB1-AMPK Signaling[EB/OL].(2025-03-28)[2025-05-13].https://www.medrxiv.org/content/10.1101/2021.11.30.21266453.点此复制
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