PMID- 25976932
OWN - NLM
STAT- MEDLINE
DCOM- 20160711
LR  - 20171116
IS  - 1478-3231 (Electronic)
IS  - 1478-3223 (Linking)
VI  - 35
IP  - 10
DP  - 2015 Oct
TI  - Small heterodimer partner attenuates profibrogenic features of hepatitis C 
      virus-infected cells.
PG  - 2233-45
LID - 10.1111/liv.12871 [doi]
AB  - BACKGROUND & AIMS: An atypical orphan nuclear receptor small heterodimer partner 
      (SHP) is known to be regulated by AMP-activated protein kinase (AMPK). Both of 
      them inhibit TGF-beta and Smad signalling and exhibit antifibrotic activity in the 
      liver. However, little is known about the protective effects of SHP and AMPK 
      against hepatitis c virus (HCV)-induced hepatic fibrosis. METHODS: Levels of SHP, 
      p-AMPK and fibrotic markers in HCV-infected human liver and in Huh-7.5 cells 
      infected with HCV genotype 2a (JFH-1) were investigated. The effect of 
      adenovirus-mediated overexpression of SHP (Ad-SHP) and AMPK activation via 
      metformin and 5-amino-1-b-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) on 
      fibrotic gene expression was evaluated in HCV-infected cells. Finally, we 
      examined the effect of Ad-SHP and AMPK activators on invasion and activation of 
      LX2 human HSCs induced by conditioned media from HCV-infected hepatocyte (CM). 
      RESULTS: In HCV-infected human livers and Huh-7.5 cells infected with HCV, SHP 
      mRNA and protein levels were diminished compared with controls, whereas 
      profibrotic factors were increased. Pharmacological AMPK activation recovered SHP 
      expression, and Ad-SHP inhibited HCV-induced fibrotic gene expression. This 
      finding was accompanied by inhibition of HCV-stimulated nuclear factor-kappa B, 
      an inducer of TGF-beta. Moreover, CytoSelect invasion assay revealed that enhanced 
      activity and invasiveness of hepatic stellate cells induced by CM. CONCLUSION: 
      These results demonstrate that overexpression of SHP and activation of AMPK 
      reverses profibrogenic features of HCV-infected cells by decreasing TGF-beta and 
      fibrotic gene expression. These findings provide a rationale for SHP as a 
      possible therapeutic target against HCV-induced hepatic fibrosis.
CI  - (c) 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
FAU - Jung, Gwon-Soo
AU  - Jung GS
AD  - Department of Internal Medicine, Kyungpook National University School of 
      Medicine, Daegu, Korea.
FAU - Jeon, Jae-Han
AU  - Jeon JH
AD  - Department of Internal Medicine, Kyungpook National University School of 
      Medicine, Daegu, Korea.
FAU - Choi, Yeon-Kyung
AU  - Choi YK
AD  - Department of Internal Medicine, Kyungpook National University School of 
      Medicine, Daegu, Korea.
FAU - Jang, Se Young
AU  - Jang SY
AD  - Department of Internal Medicine, Kyungpook National University School of 
      Medicine, Daegu, Korea.
FAU - Park, Soo Young
AU  - Park SY
AD  - Department of Internal Medicine, Kyungpook National University School of 
      Medicine, Daegu, Korea.
FAU - Kim, Mi-Kyung
AU  - Kim MK
AD  - Department of Internal Medicine, Keimyung University School of Medicine, Daegu, 
      Korea.
FAU - Shin, Eui-Cheol
AU  - Shin EC
AD  - Laboratory of Immunology and Infectious Diseases, Graduate School of Medical 
      Science and Engineering, KAIST, Daejeon, Korea.
FAU - Jeong, Won-Il
AU  - Jeong WI
AD  - Laboratory of Liver Research, Graduate School of Medical Science and Engineering, 
      KAIST, Daejeon, Korea.
FAU - Lee, In-Kyu
AU  - Lee IK
AD  - Department of Internal Medicine, Kyungpook National University School of 
      Medicine, Daegu, Korea.
FAU - Kang, Yu Na
AU  - Kang YN
AD  - Department of Pathology, Keimyung University School of Medicine, Daegu, Korea.
FAU - Park, Keun-Gyu
AU  - Park KG
AD  - Department of Internal Medicine, Kyungpook National University School of 
      Medicine, Daegu, Korea.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150603
PL  - United States
TA  - Liver Int
JT  - Liver international : official journal of the International Association for the 
      Study of the Liver
JID - 101160857
RN  - 0 (Receptors, Cytoplasmic and Nuclear)
RN  - 0 (Ribonucleotides)
RN  - 0 (Transforming Growth Factor beta)
RN  - 0 (nuclear receptor subfamily 0, group B, member 2)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - 9100L32L2N (Metformin)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - F0X88YW0YK (AICA ribonucleotide)
SB  - IM
CIN - Liver Int. 2015 Oct;35(10):2218-21. PMID: 26037155
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Aminoimidazole Carboxamide/analogs & derivatives/pharmacology
MH  - Cell Line, Tumor
MH  - Gluconeogenesis/drug effects
MH  - Hepacivirus
MH  - Hepatic Stellate Cells/metabolism
MH  - Humans
MH  - Liver Cirrhosis/*drug therapy
MH  - Metformin/pharmacology
MH  - Receptors, Cytoplasmic and Nuclear/genetics/*pharmacology
MH  - Ribonucleotides/pharmacology
MH  - Signal Transduction/drug effects
MH  - Transforming Growth Factor beta/*metabolism
OTO - NOTNLM
OT  - AMP-activated protein kinase
OT  - hepatitis C virus
OT  - liver fibrosis
OT  - small heterodimer partner
EDAT- 2015/05/16 06:00
MHDA- 2016/07/12 06:00
CRDT- 2015/05/16 06:00
PHST- 2015/01/14 00:00 [received]
PHST- 2015/05/08 00:00 [accepted]
PHST- 2015/05/16 06:00 [entrez]
PHST- 2015/05/16 06:00 [pubmed]
PHST- 2016/07/12 06:00 [medline]
AID - 10.1111/liv.12871 [doi]
PST - ppublish
SO  - Liver Int. 2015 Oct;35(10):2233-45. doi: 10.1111/liv.12871. Epub 2015 Jun 3.