PMID- 29338075
OWN - NLM
STAT- MEDLINE
DCOM- 20190808
LR  - 20211204
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 175
IP  - 9
DP  - 2018 May
TI  - Liver kinase B1/AMP-activated protein kinase-mediated regulation by 
      gentiopicroside ameliorates P2X7 receptor-dependent alcoholic hepatosteatosis.
PG  - 1451-1470
LID - 10.1111/bph.14145 [doi]
AB  - BACKGROUND AND PURPOSE: Regulating P2X7 receptor-mediated activation of NLRP3 
      inflammasomes could be a therapeutic strategy to treat alcoholic hepatosteatosis. 
      We investigated whether this process was modulated by gentiopicroside, the main 
      active secoiridoid glycoside from Gentiana manshurica Kitagawa. EXPERIMENTAL 
      APPROACH: In vivo models of acute and chronic alcoholic hepatosteatosis were 
      established by intragastrically administered ethanol or using chronic plus binge 
      ethanol feeding of Lieber-DeCarli liquid diet to male C57BL/6 mice. In vitro, 
      HepG2 cells were treated with ethanol. RAW 264.7 macrophages and murine bone 
      marrow-derived macrophages (BMDMs) were stimulated with LPS and ATP. KEY RESULTS: 
      In both the acute and chronic alcohol-induced mouse hepatosteatosis models, 
      gentiopicroside decreased serum aminotransferases and triglyceride accumulation. 
      Up-regulated SREBP1, down-regulated PPARalpha and phosphorylated acetyl-CoA 
      carboxylase caused by acute and chronic alcohol feeding were modulated by 
      gentiopicroside, through the elevation of LKB1 and AMPK. Suppression of P2X7 
      receptor-NLRP3 activation by gentiopicroside inhibited IL-1beta production. In 
      ethanol-exposed HepG2 cells, gentiopicroside reduced lipogenesis and promoted 
      lipid oxidation via activation of P2X7 receptor-NLRP3 inflammasomes. Genetic or 
      pharmacological blockade of P2X7 receptors enhanced AMPK activity and reduced 
      SREBP1 expression in ethanol-treated HepG2 cells. Gentiopicroside down-regulated 
      P2X7 receptor-mediated inflammatory responses in LPS/ATP-stimulated RAW 264.7 
      macrophages and BMDMs. IL-1beta from macrophages accelerated lipid accumulation in 
      hepatocytes. Depleting macrophages by clodronate liposomes ameliorated alcoholic 
      hepatosteatosis, and it was further alleviated by gentiopicroside. CONCLUSIONS 
      AND IMPLICATIONS: Activation of LKB1/AMPK signalling by gentiopicroside was 
      mediated by the P2X7 receptor-NLRP3 inflammasome, suggesting the therapeutic 
      value of blocking P2X7 receptors in the treatment of alcoholic hepatosteatosis.
CI  - (c) 2018 The British Pharmacological Society.
FAU - Li, Xia
AU  - Li X
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Jin, Quan
AU  - Jin Q
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Xia, Kai-Li
AU  - Xia KL
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Jiang, Min
AU  - Jiang M
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Cui, Ben-Wen
AU  - Cui BW
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Wu, Yan-Ling
AU  - Wu YL
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Song, Shun-Zong
AU  - Song SZ
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Lian, Li-Hua
AU  - Lian LH
AUID- ORCID: 0000-0002-6957-1317
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
FAU - Nan, Ji-Xing
AU  - Nan JX
AUID- ORCID: 0000-0002-6221-4309
AD  - Key Laboratory for Natural Resource of Changbai Mountain and Functional 
      Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, 
      Jilin Province, 133002, China.
AD  - Clinical Research Center, Yanbian University Hospital, Yanji, Jilin Province, 
      133002, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180309
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Iridoid Glucosides)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (PPAR alpha)
RN  - 0 (Purinergic P2X Receptor Antagonists)
RN  - 0 (Receptors, Purinergic P2X7)
RN  - 0 (Sterol Regulatory Element Binding Protein 1)
RN  - 0 (Triglycerides)
RN  - 0WE09Z21RC (gentiopicroside)
RN  - 3K9958V90M (Ethanol)
RN  - 8L70Q75FXE (Adenosine Triphosphate)
RN  - EC 2.6.1.- (Transaminases)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Stk11 protein, mouse)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Acetyl-CoA Carboxylase/metabolism
MH  - Adenosine Triphosphate
MH  - Animals
MH  - Cells, Cultured
MH  - Down-Regulation/drug effects
MH  - Ethanol/antagonists & inhibitors/pharmacology
MH  - Fatty Liver, Alcoholic/*metabolism/*prevention & control
MH  - Humans
MH  - Inflammasomes/metabolism
MH  - Interleukin-1beta/metabolism
MH  - Iridoid Glucosides/*pharmacology
MH  - Lipid Peroxidation/drug effects
MH  - Lipogenesis/drug effects
MH  - Lipopolysaccharides
MH  - Macrophages/metabolism
MH  - Male
MH  - Mice
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
MH  - PPAR alpha/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Purinergic P2X Receptor Antagonists/pharmacology
MH  - Receptors, Purinergic P2X7/drug effects/*metabolism
MH  - Sterol Regulatory Element Binding Protein 1/metabolism
MH  - Transaminases/blood
MH  - Triglycerides/blood
MH  - Up-Regulation/drug effects
PMC - PMC5900996
EDAT- 2018/01/18 06:00
MHDA- 2019/08/09 06:00
PMCR- 2019/05/01
CRDT- 2018/01/17 06:00
PHST- 2017/09/20 00:00 [received]
PHST- 2017/12/19 00:00 [revised]
PHST- 2017/12/22 00:00 [accepted]
PHST- 2018/01/18 06:00 [pubmed]
PHST- 2019/08/09 06:00 [medline]
PHST- 2018/01/17 06:00 [entrez]
PHST- 2019/05/01 00:00 [pmc-release]
AID - BPH14145 [pii]
AID - 10.1111/bph.14145 [doi]
PST - ppublish
SO  - Br J Pharmacol. 2018 May;175(9):1451-1470. doi: 10.1111/bph.14145. Epub 2018 Mar 
      9.