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

Authors: Coombes, J. D.; Choi, S. S.; Swiderska-Syn, M.; Manka, P.; Reid, D. T.; Palma, E.; Briones-Orta, M. A.; Xie, G.; Younis, R.; Kitamura, N.; Della Peruta, M.; Bitencourt, S.; Dolle, L.; Oo, Y. H.; Mi, Z.; Kuo, P. C.; Williams, R.; Chokshi, S.; Canbay, A.; Claridge, L. C.; Eksteen, B.; Diehl, A. M.; Syn, W. K.
Article Title: Osteopontin is a proximal effector of leptin-mediated non-alcoholic steatohepatitis (NASH) fibrosis
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 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.
Journal Title: Biochimica et biophysica acta
Volume: 1862
Issue: 1
ISSN: 0006-3002; 0006-3002
Publisher: Elsevier Inc  
Journal Place: Netherlands
Date Published: 2016
Start Page: 135
End Page: 144
Language: eng
Notes: LR: 20160322; CI: Copyright (c) 2015; GR: G1002552/Medical Research Council/United Kingdom; GR: K08 DK080980/DK/NIDDK NIH HHS/United States; GR: R01 DK077794/DK/NIDDK NIH HHS/United States; JID: 0217513; NIHMS734954; OID: NLM: NIHMS734954 [Available on 01/01/17]; OID: NLM: PMC4756594 [Available on 01/01/17]; OTO: NOTNLM; PMCR: 2017/01/01 00:00; 2015/08/05 [received]; 2015/10/20 [revised]; 2015/10/29 [accepted]; 2015/10/31 [aheadofprint]; ppublish