Marco A. Briones-Orta
Foundation for Liver Research
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Featured researches published by Marco A. Briones-Orta.
Biochimica et Biophysica Acta | 2016
Jason D. Coombes; Steven Sok Choi; Marzena Swiderska-Syn; Paul Manka; Danielle T. Reid; Elena Palma; Marco A. Briones-Orta; Guanhua Xie; Rasha Younis; Naoto Kitamura; Marco della Peruta; Shanna Bitencourt; Laurent Dollé; Ye Htun Oo; Zhiyong Mi; Paul C. Kuo; Roger Williams; S. Chokshi; Ali Canbay; Lee C. Claridge; Bertus Eksteen; Anna Mae Diehl; Wing Kin Syn
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.
The American Journal of the Medical Sciences | 2017
K. Mehta; Jason D. Coombes; Marco A. Briones-Orta; Paul Manka; Roger Williams; Vinood B. Patel; Wing-Kin Syn
Background: Although excess iron induces oxidative stress in the liver, it is unclear whether it directly activates the hepatic stellate cells (HSC). Materials and Methods: We evaluated the effects of excess iron on fibrogenesis and transforming growth factor beta (TGF‐&bgr;) signaling in murine HSC. Cells were treated with holotransferrin (0.005‐5 g/L) for 24 hours, with or without the iron chelator deferoxamine (10 &mgr;M). Gene expressions (&agr;‐SMA, Col1‐&agr;1, Serpine‐1, TGF‐&bgr;, Hif1‐&agr;, Tfrc and Slc40a1) were analyzed by quantitative real time‐polymerase chain reaction, whereas TfR1, ferroportin, ferritin, vimentin, collagen, TGF‐&bgr; RII and phospho‐Smad2 proteins were evaluated by immunofluorescence, Western blot and enzyme‐linked immunosorbent assay. Results: HSC expressed the iron‐uptake protein transferrin receptor 1 (TfR1) and the iron‐export protein ferroportin. Holotransferrin upregulated TfR1 expression by 1.8‐fold (P < 0.03) and ferritin accumulation (iron storage) by 2‐fold (P < 0.01), and activated HSC with 2‐fold elevations (P < 0.03) in &agr;‐SMA messenger RNA and collagen secretion, and a 1.6‐fold increase (P < 0.01) in vimentin protein. Moreover, holotransferrin activated the TGF‐&bgr; pathway with TGF‐&bgr; messenger RNA elevated 1.6‐fold (P = 0.05), and protein levels of TGF‐&bgr; RII and phospho‐Smad2 increased by 1.8‐fold (P < 0.01) and 1.6‐fold (P < 0.01), respectively. In contrast, iron chelation decreased ferritin levels by 30% (P < 0.03), inhibited collagen secretion by 60% (P < 0.01), repressed fibrogenic genes &agr;‐SMA (0.2‐fold; P < 0.05) and TGF‐&bgr; (0.4‐fold; P < 0.01) and reduced levels of TGF‐&bgr; RII and phospho‐Smad2 proteins. Conclusions: HSC express iron‐transport proteins. Holotransferrin (iron) activates HSC fibrogenesis and the TGF‐&bgr; pathway, whereas iron depletion by chelation reverses this, suggesting that this could be a useful adjunct therapy for patients with fibrosis. Further studies in primary human HSC and animal models are necessary to confirm this.
Journal of Hepatology | 2017
Paul Manka; Jason D. Coombes; L.P. Bechmann; Laurent Dollé; Marzena Swiderska-Syn; Marco A. Briones-Orta; Roger Williams; L.A. van Grunsven; Ali Canbay; Frédéric Flamant; Karine Gauthier; Wing-Kin Syn
Journal of Hepatology | 2017
Paul Manka; Jason D. Coombes; L.P. Bechmann; Laurent Dollé; Marzena Swiderska-Syn; Marco A. Briones-Orta; Roger Williams; L.A. van Grunsven; Ali Canbay; Frédéric Flamant; Karine Gauthier; Wing-Kin Syn
Archive | 2016
K. Mehta; Marco A. Briones-Orta; Paul Manka; Jason D. Coombes; Roger Williams; Vinood B. Patel; W-K. Syn
Journal of Hepatology | 2016
Jason D. Coombes; Paul Manka; Marzena Swiderska-Syn; Danielle T. Reid; A. Riva; Lee C. Claridge; Laurent Dollé; Rasha Younis; Marco A. Briones-Orta; Naoto Kitamura; K. Mehta; Zhiyong Mi; Paul C. Kuo; Roger Williams; Anna Mae Diehl; L.A. van Grunsven; S. Chokshi; Bertus Eksteen; Ali Canbay; Wing-Kin Syn
Hepatology | 2015
Jason D. Coombes; Paul Manka; Marzena Swiderska-Syn; A. Riva; Danielle T. Reid; Lee C. Claridge; Laurent Dollé; Rasha Younis; Marco A. Briones-Orta; Naoto Kitamura; Zhiyong Mi; Paul C. Kuo; Roger Williams; Anna Mae Diehl; S. Chokshi; Bertus Eksteen; Ali Canbay; Wing-Kin Syn
Hepatology | 2015
Marco A. Briones-Orta; Jason D. Coombes; Massimiliano Mellone; Rossella Rispoli; Paul Manka; Rasha Younis; Naoto Kitamura; Shannon Glaser; Gianfranco Alpini; Alberto Quaglia; Roger Williams; Salvatore Papa; Ali Canbay; Wing-Kin Syn
67. Annual Meeting of the American Association for the Study of Liver Diseases: The Liver Meeting 2016 | 2015
Jason D. Coombes; Paul Manka; Marzena Swiderska-Syn; Danielle T. Reid; A. Riva; Lee C. Claridge; Laurent Dollé; Rasha Younis; Marco A. Briones-Orta; Naoto Kitamura; K. Mehta; Zhiyong Mi; Paul C. Kuo; Roger Williams; Anna Mae Diehl; L.A. van Grunsven; S. Chokshi; Ali Canbay; Frédéric Flamant; Karine Gauthier; Bertus Eksteen; Wing-Kin Syn
Journal of Hepatology | 2014
Jason D. Coombes; Marzena Swiderska-Syn; Laurent Dollé; Danielle T. Reid; Bertus Eksteen; Lee C. Claridge; Marco A. Briones-Orta; S. Shishir; Yh Oo; A. Riva; S. Chokshi; Salvatore Papa; Zhiyong Mi; Paul C. Kuo; Roger Williams; Ali Canbay; David H. Adams; L.A. van Grunsven; Anna Mae Diehl; Steve S. Choi; Wing-Kin Syn