PMID- 29253535
OWN - NLM
STAT- MEDLINE
DCOM- 20181005
LR  - 20231101
IS  - 1090-2422 (Electronic)
IS  - 0014-4827 (Linking)
VI  - 362
IP  - 2
DP  - 2018 Jan 15
TI  - Optimizing combination of liver-enriched transcription factors and nuclear 
      receptors simultaneously favors ammonia and drug metabolism in liver cells.
PG  - 504-514
LID - S0014-4827(17)30669-9 [pii]
LID - 10.1016/j.yexcr.2017.12.015 [doi]
AB  - The HepG2 cell line is widely used in studying liver diseases because of its 
      immortalization, but its clinical application is limited by its low expression of 
      the urea synthesis key enzymes and cytochromes P450 (CYPs). On the basis of our 
      previous work, we investigated the transcriptional regulation of arginase 1 
      (Arg1) and ornithine transcarbamylase (OTC) in HepG2 cells. We also screened for 
      the optimal combination of liver enrichment transcription factors (LETFs) and 
      xenobiotic nuclear receptors that can promote the expression of key urea 
      synthases and five major CYPs in HepG2 cells. Thus, recombinant HepG2 cells were 
      established. Results showed that C/EBPbeta, not C/EBPalpha, could upregulate expression 
      of Arg1 and PGC1alpha and HNF4alpha cooperatively regulate the expression of OTC. The two 
      optimal combinations C/EBPbeta+HNF4alpha+HNF6+PXR and C/EBPbeta+HNF4alpha+HNF6+CAR were 
      selected. Compared with the control cells, the recombinant HepG2 cells modified 
      by the two optimal combinations exhibited enhanced ammonia metabolism and CYP 
      enzyme activity. Moreover, the HepG2/(C/EBPbeta+HNF4alpha+HNF6+PXR) cells more strongly 
      reduced ammonia than any other combination tested in this study. The present work 
      indicated that optimizing the combination of transcription factors will 
      simultaneously promote hepatocyte ammonia metabolism and drug metabolism. The 
      recombinant HepG2 liver cell line constructed by the optimal combination provided 
      an improved alternative means for bioartificial liver applications and drug 
      toxicity testing.
CI  - Copyright (c) 2017 Elsevier Inc. All rights reserved.
FAU - Su, Yongfa
AU  - Su Y
AD  - Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union 
      Hospital, Fuzhou, China.
FAU - Chen, Zhanfei
AU  - Chen Z
AD  - Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union 
      Hospital, Fuzhou, China.
FAU - Yan, Linlin
AU  - Yan L
AD  - Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union 
      Hospital, Fuzhou, China.
FAU - Lian, Fen
AU  - Lian F
AD  - Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union 
      Hospital, Fuzhou, China.
FAU - You, Jianhua
AU  - You J
AD  - Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union 
      Hospital, Fuzhou, China.
FAU - Wang, Xiaoqian
AU  - Wang X
AD  - Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union 
      Hospital, Fuzhou, China.
FAU - Tang, Nanhong
AU  - Tang N
AD  - Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union 
      Hospital, Fuzhou, China; Key Laboratory of Ministry of Education for 
      Gastrointestinal Cancer, Research Center for Molecular Medicine, Fujian Medical 
      University, Fuzhou, China. Electronic address: fztnh@sina.com.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20171216
PL  - United States
TA  - Exp Cell Res
JT  - Experimental cell research
JID - 0373226
RN  - 0 (CCAAT-Enhancer-Binding Proteins)
RN  - 0 (CEBPA protein, human)
RN  - 0 (HNF4A protein, human)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (PPARGC1A protein, human)
RN  - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha)
RN  - 7664-41-7 (Ammonia)
RN  - EC 2.1.3.3 (Ornithine Carbamoyltransferase)
RN  - EC 3.5.3.1 (Arginase)
SB  - IM
EIN - Exp Cell Res. 2023 Dec 15;433(2):113809. PMID: 37913573
MH  - Ammonia/metabolism/*pharmacology
MH  - Arginase/*genetics/metabolism
MH  - CCAAT-Enhancer-Binding Proteins/genetics/metabolism
MH  - Gene Expression Regulation, Neoplastic
MH  - Hep G2 Cells
MH  - Hepatocyte Nuclear Factor 4/genetics/metabolism
MH  - Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Inactivation, Metabolic/drug effects/genetics
MH  - Liver/drug effects/metabolism
MH  - Liver Neoplasms/drug therapy/*metabolism/pathology
MH  - Ornithine Carbamoyltransferase/*genetics
MH  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 
      1-alpha/genetics/metabolism
MH  - Promoter Regions, Genetic/genetics
OTO - NOTNLM
OT  - Ammonia
OT  - Cytochromes P450 (CYP)
OT  - Liver cell
OT  - Liver-enriched transcription factor (LETF)
OT  - Xenobiotics nuclear receptor
EDAT- 2017/12/19 06:00
MHDA- 2018/10/06 06:00
CRDT- 2017/12/19 06:00
PHST- 2017/11/09 00:00 [received]
PHST- 2017/12/12 00:00 [revised]
PHST- 2017/12/14 00:00 [accepted]
PHST- 2017/12/19 06:00 [pubmed]
PHST- 2018/10/06 06:00 [medline]
PHST- 2017/12/19 06:00 [entrez]
AID - S0014-4827(17)30669-9 [pii]
AID - 10.1016/j.yexcr.2017.12.015 [doi]
PST - ppublish
SO  - Exp Cell Res. 2018 Jan 15;362(2):504-514. doi: 10.1016/j.yexcr.2017.12.015. Epub 
      2017 Dec 16.