PMID- 26529285
OWN - NLM
STAT- MEDLINE
DCOM- 20190124
LR  - 20220129
IS  - 0006-3002 (Print)
IS  - 0006-3002 (Linking)
VI  - 1862
IP  - 1
DP  - 2016 Jan
TI  - Osteopontin is a proximal effector of leptin-mediated non-alcoholic 
      steatohepatitis (NASH) fibrosis.
PG  - 135-44
LID - S0925-4439(15)00328-2 [pii]
LID - 10.1016/j.bbadis.2015.10.028 [doi]
AB  - INTRODUCTION: Liver fibrosis develops when hepatic stellate cells (HSC) are 
      activated into collagen-producing myofibroblasts. In non-alcoholic 
      steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver 
      fibrosis by directly activating HSC via the hedgehog pathway. We reported that 
      hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver 
      fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in 
      NASH. METHODS: Leptin-deficient (ob/ob) and wild-type (WT) mice were fed control 
      or methionine-choline deficient (MCD) diet. Liver tissues were assessed by 
      Sirius-red, OPN and alphaSMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC 
      with stable OPN (or control) knockdown were treated with recombinant (r)leptin 
      and OPN-neutralizing or sham-aptamers. HSC response to OPN loss was assessed by 
      wound healing assay. OPN-aptamers were also added to precision-cut liver slices 
      (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN 
      neutralization abrogated fibrogenesis. RESULTS: MCD-fed WT mice developed 
      NASH-fibrosis, upregulated OPN, and accumulated alphaSMA+ cells. Conversely, MCD-fed 
      ob/ob mice developed less fibrosis and accumulated fewer alphaSMA+ and OPN+ cells. In 
      vitro, leptin-treated HSC upregulated OPN, alphaSMA, collagen 1alpha1 and TGFbeta mRNA by 
      nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and 
      transduction of dominant negative-Akt abrogated leptin-mediated OPN induction, 
      while constitutive active-Akt upregulated OPN. Finally, OPN neutralization 
      reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice. CONCLUSION: 
      OPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. 
      OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential 
      utility of targeting OPN in the treatment of patients with advanced NASH.
CI  - Copyright (c) 2015 Elsevier B.V. All rights reserved.
FAU - Coombes, Jason D
AU  - Coombes JD
AD  - Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver 
      Research, London, UK; Division of Transplantation Immunology and Mucosal Biology, 
      King's College London, UK.
FAU - Choi, Steve S
AU  - Choi SS
AD  - Division of Gastroenterology, Department of Medicine, Duke University, NC, USA; 
      Section of Gastroenterology, Department of Medicine, Durham Veteran Affairs 
      Medical Center, Durham, NC, USA.
FAU - Swiderska-Syn, Marzena
AU  - Swiderska-Syn M
AD  - Division of Gastroenterology, Department of Medicine, Duke University, NC, USA.
FAU - Manka, Paul
AU  - Manka P
AD  - Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver 
      Research, London, UK; Department of Gastroenterology and Hepatology, Essen 
      University Hospital, Essen, Germany.
FAU - Reid, Danielle T
AU  - Reid DT
AD  - Snyder Institute for Chronic Diseases, Health Research and Innovation Centre 
      (HRIC), University of Calgary, Canada.
FAU - Palma, Elena
AU  - Palma E
AD  - Division of Transplantation Immunology and Mucosal Biology, King's College 
      London, UK; Viral Hepatitis and Alcohol Research Group, The Institute of 
      Hepatology, Foundation for Liver Research, London, UK.
FAU - Briones-Orta, Marco A
AU  - Briones-Orta MA
AD  - Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver 
      Research, London, UK; Division of Transplantation Immunology and Mucosal Biology, 
      King's College London, UK.
FAU - Xie, Guanhua
AU  - Xie G
AD  - Division of Gastroenterology, Department of Medicine, Duke University, NC, USA.
FAU - Younis, Rasha
AU  - Younis R
AD  - Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver 
      Research, London, UK.
FAU - Kitamura, Naoto
AU  - Kitamura N
AD  - Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver 
      Research, London, UK.
FAU - Della Peruta, Marco
AU  - Della Peruta M
AD  - Viral Hepatitis and Alcohol Research Group, The Institute of Hepatology, 
      Foundation for Liver Research, London, UK.
FAU - Bitencourt, Shanna
AU  - Bitencourt S
AD  - Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Faculty of 
      Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
FAU - Dolle, Laurent
AU  - Dolle L
AD  - Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Faculty of 
      Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
FAU - Oo, Ye Htun
AU  - Oo YH
AD  - Centre for Liver Research and NIHR Birmingham Biomedical Research Unit, 
      University of Birmingham, Birmingham, UK.
FAU - Mi, Zhiyong
AU  - Mi Z
AD  - Department of Surgery, Loyola University, Chicago, USA.
FAU - Kuo, Paul C
AU  - Kuo PC
AD  - Department of Surgery, Loyola University, Chicago, USA.
FAU - Williams, Roger
AU  - Williams R
AD  - Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver 
      Research, London, UK; Division of Transplantation Immunology and Mucosal Biology, 
      King's College London, UK.
FAU - Chokshi, Shilpa
AU  - Chokshi S
AD  - Division of Transplantation Immunology and Mucosal Biology, King's College 
      London, UK; Viral Hepatitis and Alcohol Research Group, The Institute of 
      Hepatology, Foundation for Liver Research, London, UK.
FAU - Canbay, Ali
AU  - Canbay A
AD  - Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, 
      Germany.
FAU - Claridge, Lee C
AU  - Claridge LC
AD  - Liver Unit, St James University Hospital, Leeds, UK.
FAU - Eksteen, Bertus
AU  - Eksteen B
AD  - Snyder Institute for Chronic Diseases, Health Research and Innovation Centre 
      (HRIC), University of Calgary, Canada.
FAU - Diehl, Anna Mae
AU  - Diehl AM
AD  - Division of Gastroenterology, Department of Medicine, Duke University, NC, USA.
FAU - Syn, Wing-Kin
AU  - Syn WK
AD  - Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver 
      Research, London, UK; Division of Transplantation Immunology and Mucosal Biology, 
      King's College London, UK; Department of Surgery, Loyola University, Chicago, 
      USA; Liver Unit, Barts Health NHS Trust, London, UK; Department of Physiology, 
      University of the Basque Country, Bilbao, Spain. Electronic address: 
      wsyn@doctors.org.uk.
LA  - eng
GR  - G1002552/MRC_/Medical Research Council/United Kingdom
GR  - K08 DK080980/DK/NIDDK NIH HHS/United States
GR  - R01 DK077794/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 - 20151031
PL  - Netherlands
TA  - Biochim Biophys Acta
JT  - Biochimica et biophysica acta
JID - 0217513
RN  - 0 (Leptin)
RN  - 106441-73-0 (Osteopontin)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Cells, Cultured
MH  - Gene Deletion
MH  - Hepatocytes/metabolism/pathology
MH  - Leptin/genetics/*metabolism
MH  - Liver/metabolism/*pathology
MH  - Liver Cirrhosis/genetics/*metabolism/pathology
MH  - Male
MH  - Mice, Inbred C57BL
MH  - Non-alcoholic Fatty Liver Disease/genetics/*metabolism/pathology
MH  - Osteopontin/genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction
MH  - Up-Regulation
PMC - PMC4756594
MID - NIHMS734954
OTO - NOTNLM
OT  - Adipokine
OT  - Fibrosis
OT  - Hepatic
OT  - Signaling
EDAT- 2015/11/04 06:00
MHDA- 2019/01/25 06:00
PMCR- 2017/01/01
CRDT- 2015/11/04 06:00
PHST- 2015/08/05 00:00 [received]
PHST- 2015/10/20 00:00 [revised]
PHST- 2015/10/29 00:00 [accepted]
PHST- 2015/11/04 06:00 [entrez]
PHST- 2015/11/04 06:00 [pubmed]
PHST- 2019/01/25 06:00 [medline]
PHST- 2017/01/01 00:00 [pmc-release]
AID - S0925-4439(15)00328-2 [pii]
AID - 10.1016/j.bbadis.2015.10.028 [doi]
PST - ppublish
SO  - Biochim Biophys Acta. 2016 Jan;1862(1):135-44. doi: 10.1016/j.bbadis.2015.10.028. 
      Epub 2015 Oct 31.