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Biochim Biophys Acta. 2016 Jan;1862(1):135-44. doi: 10.1016/j.bbadis.2015.10.028. Epub 2015 Oct 31.

Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis.

Author information

1
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.
2
Division of Gastroenterology, Department of Medicine, Duke University, NC, USA; Section of Gastroenterology, Department of Medicine, Durham Veteran Affairs Medical Center, Durham, NC, USA.
3
Division of Gastroenterology, Department of Medicine, Duke University, NC, USA.
4
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK; Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.
5
Snyder Institute for Chronic Diseases, Health Research and Innovation Centre (HRIC), University of Calgary, Canada.
6
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.
7
Regeneration and Repair Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
8
Viral Hepatitis and Alcohol Research Group, The Institute of Hepatology, Foundation for Liver Research, London, UK.
9
Liver Cell Biology Lab (LIVR), Department of Cell Biology (CYTO), Faculty of Medicine and Pharmacy, Vrije Universiteit Brussel, Brussels, Belgium.
10
Centre for Liver Research and NIHR Birmingham Biomedical Research Unit, University of Birmingham, Birmingham, UK.
11
Department of Surgery, Loyola University, Chicago, USA.
12
Department of Gastroenterology and Hepatology, Essen University Hospital, Essen, Germany.
13
Liver Unit, St James University Hospital, Leeds, UK.
14
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.

Abstract

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 αSMA 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 αSMA+ cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer αSMA+ and OPN+ cells. In vitro, leptin-treated HSC upregulated OPN, αSMA, collagen 1α1 and TGFβ 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.

KEYWORDS:

Adipokine; Fibrosis; Hepatic; Signaling

PMID:
26529285
PMCID:
PMC4756594
DOI:
10.1016/j.bbadis.2015.10.028
[Indexed for MEDLINE]
Free PMC Article

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