PMID- 29391755
OWN - NLM
STAT- MEDLINE
DCOM- 20180910
LR  - 20210503
IS  - 2219-2840 (Electronic)
IS  - 1007-9327 (Print)
IS  - 1007-9327 (Linking)
VI  - 24
IP  - 3
DP  - 2018 Jan 21
TI  - circRNA_0046366 inhibits hepatocellular steatosis by normalization of PPAR 
      signaling.
PG  - 323-337
LID - 10.3748/wjg.v24.i3.323 [doi]
AB  - AIM: To investigate micro (mi)R-34a-antagonizing circular (circ)RNA that 
      underlies hepatocellular steatosis. METHODS: The effect of circRNA on miR-34a was 
      recognized by the miRNA response element (MRE), and validated by the 
      dual-luciferase reporter assay. Its association with hepatocellular steatosis was 
      investigated in HepG2-based hepatocellular steatosis induced by free fatty acids 
      (FFAs; 2:1 oleate:palmitate) stimulation. After normalization of the 
      steatosis-related circRNA by expression vector, analysis of miR-34a activity, 
      peroxisome proliferator-activated receptor (PPAR)alpha level, and expression of 
      downstream genes were carried out so as to reveal its impact on the miR-34a/PPARalpha 
      regulatory system. Both triglyceride (TG) assessment and cytopathological 
      manifestations uncovered the role of circRNA in miR-34a-dependent 
      hepatosteatogenesis. RESULTS: Bioinformatic and functional analysis verified 
      circRNA_0046366 to antagonize the activity of miR-34a via MRE-based 
      complementation. In contrast to its lowered level during FFA-induced 
      hepatocellular steatosis, circRNA_0046366 up-regulation abolished the 
      miR-34a-dependent inhibition of PPARalpha that played a critical role in metabolic 
      signaling pathways. PPARalpha restoration exerted transcriptional improvement to 
      multiple genes responsible for lipid metabolism. TG-specific lipolytic genes 
      [carnitine palmitoyltransferase 1A (CPT1A) and solute-carrier family 27A 
      (SLC27A)] among these showed significant increase in their expression levels. The 
      circRNA_0046366-related rebalancing of lipid homeostasis led to dramatic 
      reduction of TG content, and resulted in the ameliorated phenotype of 
      hepatocellular steatosis. CONCLUSION: Dysregulation of 
      circRNA_0046366/miR-34a/PPARalpha signaling may be a novel epigenetic mechanism 
      underlying hepatocellular steatosis. circRNA_0046366 serves as a potential target 
      for the treatment of hepatic steatosis.
FAU - Guo, Xing-Ya
AU  - Guo XY
AD  - Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University 
      School of Medicine, Shanghai 200092, China.
FAU - Sun, Fang
AU  - Sun F
AD  - Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University 
      School of Medicine, Shanghai 200092, China.
FAU - Chen, Jian-Neng
AU  - Chen JN
AD  - Department of Hepatology, Zhengxing Hospital, Zhangzhou 363000, Fujian Province, 
      China.
FAU - Wang, Yu-Qin
AU  - Wang YQ
AD  - Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University 
      School of Medicine, Shanghai 200092, China.
FAU - Pan, Qin
AU  - Pan Q
AD  - Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University 
      School of Medicine, Shanghai 200092, China. panqin@xinhuamed.com.cn.
FAU - Fan, Jian-Gao
AU  - Fan JG
AD  - Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University 
      School of Medicine, Shanghai 200092, China.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - World J Gastroenterol
JT  - World journal of gastroenterology
JID - 100883448
RN  - 0 (Fatty Acid Transport Proteins)
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (MIRN34 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - 0 (PPAR alpha)
RN  - 0 (RNA, Circular)
RN  - 0 (RNA, Messenger)
RN  - 0 (SLC27A4 protein, human)
RN  - 0 (Triglycerides)
RN  - 63231-63-0 (RNA)
RN  - EC 2.3.1.21 (CPT1A protein, human)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
SB  - IM
MH  - Carnitine O-Palmitoyltransferase/metabolism
MH  - Fatty Acid Transport Proteins/metabolism
MH  - Fatty Acids, Nonesterified/metabolism
MH  - Hep G2 Cells
MH  - Humans
MH  - Lipid Metabolism/genetics
MH  - Liver/cytology/metabolism
MH  - Metabolic Networks and Pathways/*genetics
MH  - MicroRNAs/*genetics/metabolism
MH  - Non-alcoholic Fatty Liver Disease/etiology/*genetics/pathology
MH  - PPAR alpha/*genetics/metabolism
MH  - RNA/genetics/*metabolism
MH  - RNA, Circular
MH  - RNA, Messenger/metabolism
MH  - Response Elements/genetics
MH  - Triglycerides/metabolism
MH  - Up-Regulation
PMC - PMC5776394
OTO - NOTNLM
OT  - Hepatocytes
OT  - Peroxisome proliferator-activated receptor alpha
OT  - Steatosis
OT  - circRNA_0046366
OT  - miR-34a
COIS- Conflict-of-interest statement: No conflict of interest is declared for each 
      author of the manuscript.
EDAT- 2018/02/03 06:00
MHDA- 2018/09/11 06:00
PMCR- 2018/01/21
CRDT- 2018/02/03 06:00
PHST- 2017/10/07 00:00 [received]
PHST- 2017/11/15 00:00 [revised]
PHST- 2017/11/27 00:00 [accepted]
PHST- 2018/02/03 06:00 [entrez]
PHST- 2018/02/03 06:00 [pubmed]
PHST- 2018/09/11 06:00 [medline]
PHST- 2018/01/21 00:00 [pmc-release]
AID - 10.3748/wjg.v24.i3.323 [doi]
PST - ppublish
SO  - World J Gastroenterol. 2018 Jan 21;24(3):323-337. doi: 10.3748/wjg.v24.i3.323.