PMID- 30248539
OWN - NLM
STAT- MEDLINE
DCOM- 20190301
LR  - 20190301
IS  - 1950-6007 (Electronic)
IS  - 0753-3322 (Linking)
VI  - 108
DP  - 2018 Dec
TI  - Effect of silibinin on CFLAR-JNK pathway in oleic acid-treated HepG2 cells.
PG  - 716-723
LID - S0753-3322(18)33548-0 [pii]
LID - 10.1016/j.biopha.2018.09.089 [doi]
AB  - AIMS: Silibinin is a flavonolignan from milk thistle with many pharmacological 
      activities including lipid-lowering and antioxidant. Caspase 8 and Fas-associated 
      protein with death domain-like apoptosis regulator (CFLAR) is an important target 
      gene in regulating non-alcoholic steatohepatitis (NASH). At present, the effect 
      of silibinin on CFLAR-JNK pathway related to NASH was unknown. Here the effect of 
      silibinin on CFLAR-JNK pathway and its downstream target genes involved in lipid 
      metabolism, glucose uptake, oxidative stress and inflammatory response were 
      studied in oleic acid (OA)-treated HepG2 cells. MAIN METHODS: OA-treated HepG2 
      cells were employed as a in vitro model of steatosis, insulin resistance and 
      oxidative stress. The model cells were then treated by silibinin (5, 20, 50, and 
      100 muM) for 24 h and detected for the related indicators as follows: (1) cellular 
      triglycerides (TG), nitric oxide (NO) and glucose uptake; (2) the mRNA levels of 
      the sterol regulatory element binding protein-1C (SREBP-1C), patatin-like 
      phospholipase domain containing 3 (PNPLA3) and peroxisome proliferator activated 
      receptor-alpha (PPARalpha); (3) the protein levels of PPARalpha, SREBP-1C, PNPLA3, CFLAR, 
      phosphorylated c-Jun N-terminal kinase (pJNK), phosphatidylinositol 3-kinase 
      (PI3K), phosphorylated serine-threonine protein kinase (pAKT), nuclear factor 
      E2-related factor 2 (NRF2), cytochrome P450 2E1 (CYP2E1) and 4A (CYP4A). KEY 
      FINDINGS: Compared to the control, OA-treatment led to a result as follows: (1) 
      increased the intracellular levels of TG and NO; (2) up-regulated the protein 
      expression of SREBP-1C, PNPLA3, pJNK, CYP 2E1 and CYP 4A; (3) decreased the 
      uptake of 2-NBDG; (4) down-regulated the protein expression of CFLAR, PPARalpha, 
      PI3K, pAKT and NRF2. Compared to OA-treated HepG2 cells, silibinin treatment 
      could improve the indicators as follows: (1) decreased the intracellular levels 
      of TG and NO; (2) down-regulated the protein expression of SREBP-1C, PNPLA3, 
      pJNK, CYP 2E1 and CYP 4A; (3) increased the uptake of 2-NBDG; (4) up-regulated 
      the protein expression of CFLAR, PPARalpha, PI3K, pAKT and NRF2. SIGNIFICANCE: 
      Silibinin can ameliorate some metabolic alterations and induce some molecular 
      changes by activating the CFLAR-JNK pathway and thereby regulating its downstream 
      target genes involved in lipid metabolism (PPARalpha, SREBP-1C and PNPLA3), glucose 
      uptake (PI3K-AKT), oxidative stress (NRF2, CYP2E1, CYP4A) and inflammatory 
      response(NO) in OA-treated HepG2 cells demonstrating its possible use in 
      ameliorating various symptoms of NASH.
CI  - Copyright (c) 2018 Elsevier Masson SAS. All rights reserved.
FAU - Liu, Yayun
AU  - Liu Y
AD  - Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, 
      National & Local Joint Engineering Research Center of High-throughput Drug 
      Screening Technology, Hubei University, Wuhan, Hubei, 430062, PR China.
FAU - Yu, Qingqing
AU  - Yu Q
AD  - Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, 
      National & Local Joint Engineering Research Center of High-throughput Drug 
      Screening Technology, Hubei University, Wuhan, Hubei, 430062, PR China.
FAU - Chen, Yong
AU  - Chen Y
AD  - Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, 
      National & Local Joint Engineering Research Center of High-throughput Drug 
      Screening Technology, Hubei University, Wuhan, Hubei, 430062, PR China. 
      Electronic address: cy101610@qq.com.
LA  - eng
PT  - Journal Article
DEP - 20180921
PL  - France
TA  - Biomed Pharmacother
JT  - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
JID - 8213295
RN  - 0 (CASP8 and FADD-Like Apoptosis Regulating Protein)
RN  - 0 (CFLAR protein, human)
RN  - 0 (Triglycerides)
RN  - 2UMI9U37CP (Oleic Acid)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 4RKY41TBTF (Silybin)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - CASP8 and FADD-Like Apoptosis Regulating Protein/*metabolism
MH  - Cell Line, Tumor
MH  - Down-Regulation/drug effects
MH  - Glucose/metabolism
MH  - Hep G2 Cells
MH  - Humans
MH  - Inflammation/drug therapy
MH  - Insulin Resistance/physiology
MH  - Lipid Metabolism/drug effects
MH  - MAP Kinase Signaling System/*drug effects
MH  - Nitric Oxide/metabolism
MH  - Oleic Acid/*pharmacology
MH  - Oxidative Stress/drug effects
MH  - Signal Transduction/drug effects
MH  - Silybin/*pharmacology
MH  - Triglycerides/blood
MH  - Up-Regulation/drug effects
OTO - NOTNLM
OT  - CFLAR
OT  - HepG2 cells
OT  - NASH
OT  - NRF2
OT  - Silibinin
EDAT- 2018/09/25 06:00
MHDA- 2019/03/02 06:00
CRDT- 2018/09/25 06:00
PHST- 2018/05/29 00:00 [received]
PHST- 2018/09/15 00:00 [revised]
PHST- 2018/09/16 00:00 [accepted]
PHST- 2018/09/25 06:00 [pubmed]
PHST- 2019/03/02 06:00 [medline]
PHST- 2018/09/25 06:00 [entrez]
AID - S0753-3322(18)33548-0 [pii]
AID - 10.1016/j.biopha.2018.09.089 [doi]
PST - ppublish
SO  - Biomed Pharmacother. 2018 Dec;108:716-723. doi: 10.1016/j.biopha.2018.09.089. 
      Epub 2018 Sep 21.