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The let-7/lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

Abstract The let-7/lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs (miRNAs) in different human disorders and cancer development. This study evaluated the role of the let-7/lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly downregulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (hHSCs) with lipopolysaccharide (LPS) and TGF-β significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibrobalstic activation of cultured hHSCs induced by LPS and transforming growth factor-β (TGF-β), as evidenced by repressed ACTA2, COL1A1, TIMP1, and FN1; this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that lin28b and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, lin28b deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by lin28b is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/lin28 axis as an important regulator of HSC activation, as well as its upstream modulators and down-stream targets, will provide insights into the involvement of altered miRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases.
PMID
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Authors

Mayor MeshTerms
Keywords

HMGA2

alcoholic liver diseases

fibroblast

gene knockout

hepatic stellate cell (HSC)

let-7

lin28

liver injury

microRNA (miRNA)

Journal Title the journal of biological chemistry
Publication Year Start




PMID- 28536261
OWN - NLM
STAT- Publisher
DA  - 20170524
LR  - 20170524
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Linking)
DP  - 2017 May 23
TI  - The let-7/lin28 axis regulates activation of hepatic stellate cells in alcoholic 
      liver injury.
LID - jbc.M116.773291 [pii]
LID - 10.1074/jbc.M116.773291 [doi]
AB  - The let-7/lin28 axis is associated with the regulation of key cellular regulatory
      genes known as microRNAs (miRNAs) in different human disorders and cancer
      development. This study evaluated the role of the let-7/lin28 axis in regulating 
      a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We
      identified that ethanol feeding significantly downregulated several members of
      the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the
      treatment of human hepatic stellate cells (hHSCs) with lipopolysaccharide (LPS)
      and TGF-beta significantly decreased the expressions of let-7a and let-7b.
      Conversely, overexpression of let-7a and let-7b suppressed the myofibrobalstic
      activation of cultured hHSCs induced by LPS and transforming growth factor-beta
      (TGF-beta), as evidenced by repressed ACTA2, COL1A1, TIMP1, and FN1; this
      supports the notion that HSC activation is controlled by let-7. A combination of 
      bioinformatics, dual-luciferase reporter assay, and Western blot analysis
      revealed that lin28b and high-mobility group AT-hook (HMGA2) were the direct
      targets of let-7a and let-7b. Furthermore, lin28b deficiency increased the
      expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis 
      in mice with alcoholic liver injury. This feedback regulation of let-7 by lin28b 
      is verified in hepatic stellate cells isolated by laser capture microdissection
      from the model. The identification of the let-7/lin28 axis as an important
      regulator of HSC activation, as well as its upstream modulators and down-stream
      targets, will provide insights into the involvement of altered miRNA expression
      in contributing to the pathogenesis of alcoholic liver fibrosis and novel
      therapeutic approaches for human alcoholic liver diseases.
CI  - Copyright (c) 2017, The American Society for Biochemistry and Molecular Biology.
FAU - McDaniel, Kelly
AU  - McDaniel K
AD  - Central Texas Veterans Health Care System, United States.
FAU - Huang, Li
AU  - Huang L
AD  - Sun Yat-sen University, China.
FAU - Sato, Keisaku
AU  - Sato K
AD  - Texas A&M University.
FAU - Wu, Nan
AU  - Wu N
AD  - Texas A&M University.
FAU - Annable, Tami
AU  - Annable T
AD  - Temple Bioscience Institute, United States.
FAU - Zhou, Tianhao
AU  - Zhou T
AD  - Texas A&M University.
FAU - Ramos-Lorenzo, Sugeily
AU  - Ramos-Lorenzo S
AD  - Baylor Scott & White Health.
FAU - Wan, Ying
AU  - Wan Y
AD  - Baylor Scott & White Health.
FAU - Huang, Qiaobing
AU  - Huang Q
AD  - Southern Medical University, China.
FAU - Francis, Heather
AU  - Francis H
AD  - Texas A&M University.
FAU - Glaser, Shannon
AU  - Glaser S
AD  - Texas A&M University.
FAU - Tsukamoto, Hidekazu
AU  - Tsukamoto H
AD  - Keck School of Medicine of the University of Southern California, United States.
FAU - Alpini, Gianfranco
AU  - Alpini G
AD  - Texas A&M University; [email protected]
FAU - Meng, Fanyin
AU  - Meng F
AD  - Baylor Scott & White Health.
LA  - eng
PT  - Journal Article
DEP - 20170523
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
OTO - NOTNLM
OT  - HMGA2
OT  - alcoholic liver diseases
OT  - fibroblast
OT  - gene knockout
OT  - hepatic stellate cell (HSC)
OT  - let-7
OT  - lin28
OT  - liver injury
OT  - microRNA (miRNA)
EDAT- 2017/05/26 06:00
MHDA- 2017/05/26 06:00
CRDT- 2017/05/25 06:00
PHST- 2016/12/20 [received]
PHST- 2017/05/23 [accepted]
AID - M116.773291 [pii]
AID - 10.1074/jbc.M116.773291 [doi]
PST - aheadofprint
SO  - J Biol Chem. 2017 May 23. pii: jbc.M116.773291. doi: 10.1074/jbc.M116.773291.

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