TY - JOUR
T1 - Insight into molecular mechanisms underlying hepatic dysfunction in severe COVID-19 patients using systems biology
AU - Hammoudeh, Sarah Musa
AU - Hammoudeh, Arabella Musa
AU - Bhamidimarri, Poorna Manasa
AU - Mahboub, Bassam
AU - Halwani, Rabih
AU - Hamid, Qutayba
AU - Rahmani, Mohamed
AU - Hamoudi, Rifat
N1 - Funding Information:
Supported by The University of Sharjah, No. CoV19-0308, No. CoV19-0307 and No: 1901090254;
Funding Information:
Sharjah Research Academy, No: MED001; and Al-Jalila Foundation Seed Grant, No. AJF202019.
Publisher Copyright:
© The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
PY - 2021/6/7
Y1 - 2021/6/7
N2 - BACKGROUND The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients. AIM To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction. METHODS The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR. RESULTS Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction. CONCLUSION Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.
AB - BACKGROUND The coronavirus disease 2019 (COVID-19), a pandemic contributing to more than 105 million cases and more than 2.3 million deaths worldwide, was described to be frequently accompanied by extrapulmonary manifestations, including liver dysfunction. Liver dysfunction and elevated liver enzymes were observed in about 53% of COVID-19 patients. AIM To gain insight into transcriptional abnormalities in liver tissue of severe COVID-19 patients that may result in liver dysfunction. METHODS The transcriptome of liver autopsy samples from severe COVID-19 patients against those of non-COVID donors was analyzed. Differentially expressed genes were identified from normalized RNA-seq data and analyzed for the enrichment of functional clusters and pathways. The differentially expressed genes were then compared against the genetic signatures of liver diseases including cirrhosis, fibrosis, non-alcoholic fatty liver disease (NAFLD), and hepatitis A/B/C. Gene expression of some differentially expressed genes was assessed in the blood samples of severe COVID-19 patients with liver dysfunction using qRT-PCR. RESULTS Analysis of the differential transcriptome of the liver tissue of severe COVID-19 patients revealed a significant upregulation of transcripts implicated in tissue remodeling including G-coupled protein receptors family genes, DNAJB1, IGF2, EGFR, and HDGF. Concordantly, the differential transcriptome of severe COVID-19 liver tissues substantially overlapped with the disease signature of liver diseases characterized with pathological tissue remodeling (liver cirrhosis, Fibrosis, NAFLD, and hepatitis A/B/C). Moreover, we observed a significant suppression of transcripts implicated in metabolic pathways as well as mitochondrial function, including cytochrome P450 family members, ACAD11, CIDEB, GNMT, and GPAM. Consequently, drug and xenobiotics metabolism pathways are significantly suppressed suggesting a decrease in liver detoxification capacity. In correspondence with the RNA-seq data analysis, we observed a significant upregulation of DNAJB1 and HSP90AB1 as well as significant downregulation of CYP39A1 in the blood plasma of severe COVID-19 patients with liver dysfunction. CONCLUSION Severe COVID-19 patients appear to experience significant transcriptional shift that may ensue tissue remodeling, mitochondrial dysfunction and lower hepatic detoxification resulting in the clinically observed liver dysfunction.
KW - COVID-19
KW - Drug metabolism
KW - Hepatic detoxification
KW - Hepatic dysfunction
KW - Metabolic pathways
KW - Tissue remodeling
UR - http://www.scopus.com/inward/record.url?scp=85106702781&partnerID=8YFLogxK
U2 - 10.3748/wjg.v27.i21.2850
DO - 10.3748/wjg.v27.i21.2850
M3 - Article
C2 - 34135558
AN - SCOPUS:85106702781
SN - 1007-9327
VL - 27
SP - 2850
EP - 2870
JO - World Journal of Gastroenterology
JF - World Journal of Gastroenterology
IS - 21
ER -
