Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal
Open Access
Naoki Ikenaga1, Zhen-Wei Peng1,2, Kahini A Vaid1, Susan B Liu1, Shuhei Yoshida1, Deanna Y Sverdlov1, Amanda Mikels-Vigdal3, Victoria Smith3, Detlef Schuppan1,4, Yury V Popov1
1Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
2Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
3Gilead Sciences, Foster City, California, USA
4Institute of Translational Immunology and Research Center for Immune Therapy, University Medical Center, Mainz, Germany
Correspondence to Dr Yury V Popov, Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02115, USA; ypopov{at}bidmc.harvard.edu
Received 21 June 2016
Revised 7 December 2016
Accepted 18 December 2016
Published Online First 10 January 2017
Abstract
Background/Aims We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice.
Methods Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2−/− and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro.
Results LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen crosslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2−/− and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment.
Conclusions LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and biliary fibrosis and promotes fibrosis reversal.
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作者: StephenW 时间: 2017-1-11 22:35
Gut doi:10.1136 / gutjnl-2016-312473
肝脏病学
原文
赖氨酰氧化酶样2(LOXL2)的选择性靶向抑制肝纤维化进展并加速其逆转
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Naoki Ikenaga1,Zhen-Wei Peng1,2,Kahini A Vaid1,Susan B Liu1,Shuhei Yoshida1,Deanna Y Sverdlov1,Amanda Mikels-Vigdal3,Victoria Smith3,Detlef Schuppan1,4,Yury V Popov1
通讯作者:Yury V Popov博士,消化内科和肝病学部,Beth Israel Deaconess Medical Center,Harvard Medical School,330 Brookline Avenue,Boston,MA 02115,USA; ypopov {at} bidmc.harvard.edu