PMID- 29625129
OWN - NLM
STAT- MEDLINE
DCOM- 20190220
LR  - 20190802
IS  - 1532-8600 (Electronic)
IS  - 0026-0495 (Print)
IS  - 0026-0495 (Linking)
VI  - 85
DP  - 2018 Aug
TI  - A negative feedback loop between microRNA-378 and Nrf1 promotes the development 
      of hepatosteatosis in mice treated with a high fat diet.
PG  - 183-191
LID - S0026-0495(18)30095-7 [pii]
LID - 10.1016/j.metabol.2018.03.023 [doi]
AB  - BACKGROUNDS: The incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly 
      increasing due to the prevalence of obesity. NAFLD is a major risk factor of 
      hepatocellular carcinoma (HCC). Even with successful surgical removal, the 
      presence of NAFLD is associated with an increased recurrence of HCC. Despite the 
      extensive study of NAFLD, its underlying mechanism(s) remains essentially unknown 
      and there are no FDA-approved drugs for its treatment. Alterations in microRNA 
      (miR) expression have been observed in human fatty livers. However, regulatory 
      mechanism(s) of miRNA biogenesis and their role in regulating the development of 
      NAFLD is poorly described. METHODS: We used immunohistochemistry, luciferase 
      assays and immunoblotting to study the regulatory mechanism of miR-378 
      biogenesis. Wild-type mice kept on a high fat diet (HFD) were injected with 
      miR-378 inhibitors or a mini-circle expression system containing miR-378 to study 
      loss and gain-of functions of miR-378. RESULTS: miR-378 was significantly 
      increased in fatty livers of dietary obese mice and human hepatoma HepG2 cells 
      with accumulated lipid. Further studies identified NRF1 (Nuclear receptor factor 
      1), a key regulator of fatty acid oxidation (FAO), as a direct target of miR-378. 
      Overexpression of miR-378 impaired FAO and promoted lipid accumulation in murine 
      hepatoma Hepa1-6 cells. In contrast, knockdown of miR-378 using its ASO 
      (anti-sense oligo) improved FAO and reduced intracellular lipid content in 
      Hepa1-6 cells. Liver-specific expression of miR-378 impaired FAO, which 
      subsequently promoted the development of hepatosteatosis. Antagonizing miR-378 
      via injecting miR-378-ASO into HFD-treated mice led to increased expression of 
      Nrf1, improved FAO and decreased hepatosteatosis. Additional knockdown of 
      up-regulated Nrf1 offset the effects of miR-378-ASO, suggesting that Nrf1 
      mediated the inhibitory effect of miR-378-ASO on hepatosteatosis. Furthermore, 
      Nrf1 was identified as a transcriptional repressor of miR-378. Ablation of Nrf1 
      using its shRNA in livers led to increased miR-378, which subsequently resulted 
      in reduced FAO and elevated hepatic lipid content. CONCLUSIONS: These findings 
      identified a negative feedback loop between miR-378 and Nrf1 that promotes the 
      pathogenesis of hepatosteatosis, and suggests the use of miR-378 as a potential 
      therapeutic target for NAFLD.
CI  - Copyright (c) 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Zhang, Tianpeng
AU  - Zhang T
AD  - Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
FAU - Zhao, Xiaoling
AU  - Zhao X
AD  - McLab, South San Francisco, CA 94080, USA.
FAU - Steer, Clifford J
AU  - Steer CJ
AD  - Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; 
      Department of Genetics, Cell Biology and Development, University of Minnesota, 
      Minneapolis, MN 55455, USA.
FAU - Yan, Guiqin
AU  - Yan G
AD  - College of Life and Biological Sciences, Shanxi Normal University, Linfen City 
      041000, China. Electronic address: gqyan@126.com.
FAU - Song, Guisheng
AU  - Song G
AD  - Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA; 
      McLab, South San Francisco, CA 94080, USA; College of Life and Biological 
      Sciences, Shanxi Normal University, Linfen City 041000, China. Electronic 
      address: gsong@umn.edu.
LA  - eng
GR  - R01 DK102601/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180403
PL  - United States
TA  - Metabolism
JT  - Metabolism: clinical and experimental
JID - 0375267
RN  - 0 (MIRN378 microRNA, mouse)
RN  - 0 (MicroRNAs)
RN  - 0 (Nrf1 protein, mouse)
RN  - 0 (Nuclear Respiratory Factor 1)
SB  - IM
MH  - Animals
MH  - Diet, High-Fat/*adverse effects
MH  - Feedback, Physiological/*physiology
MH  - Hep G2 Cells
MH  - Humans
MH  - Lipid Metabolism
MH  - Liver/metabolism
MH  - Mice
MH  - MicroRNAs/genetics/*metabolism
MH  - Non-alcoholic Fatty Liver Disease/etiology/genetics/*metabolism
MH  - Nuclear Respiratory Factor 1/genetics/*metabolism
MH  - Obesity/genetics/*metabolism
PMC - PMC6062470
MID - NIHMS957749
OTO - NOTNLM
OT  - Fatty acid oxidation
OT  - Hepatosteatosis
OT  - MicroRNA
OT  - Transcription regulation
COIS- Competing interests The authors declare that they have no competing interests
EDAT- 2018/04/07 06:00
MHDA- 2019/03/21 06:00
PMCR- 2019/08/01
CRDT- 2018/04/07 06:00
PHST- 2018/02/05 00:00 [received]
PHST- 2018/03/02 00:00 [revised]
PHST- 2018/03/24 00:00 [accepted]
PHST- 2018/04/07 06:00 [pubmed]
PHST- 2019/03/21 06:00 [medline]
PHST- 2018/04/07 06:00 [entrez]
PHST- 2019/08/01 00:00 [pmc-release]
AID - S0026-0495(18)30095-7 [pii]
AID - 10.1016/j.metabol.2018.03.023 [doi]
PST - ppublish
SO  - Metabolism. 2018 Aug;85:183-191. doi: 10.1016/j.metabol.2018.03.023. Epub 2018 
      Apr 3.