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Angiopoietin-2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease.

  • Lefere, Sander1
  • Van de Velde, Frederique2
  • Hoorens, Anne3
  • Raevens, Sarah1
  • Van Campenhout, Sanne1
  • Vandierendonck, Astrid1
  • Neyt, Sara4
  • Vandeghinste, Bert4
  • Vanhove, Christian5
  • Debbaut, Charlotte5
  • Verhelst, Xavier1
  • Van Dorpe, Jo3
  • Van Steenkiste, Christophe1
  • Casteleyn, Christophe6, 7
  • Lapauw, Bruno2
  • Van Vlierberghe, Hans1
  • Geerts, Anja1
  • Devisscher, Lindsey1
  • 1 Department of Gastroenterology and Hepatology, Hepatology Research Unit, Ghent University, Ghent, Belgium. , (Belgium)
  • 2 Department of Endocrinology, Ghent University, Ghent, Belgium. , (Belgium)
  • 3 Department of Pathology, Ghent University, Ghent, Belgium. , (Belgium)
  • 4 MOLECUBES NV, Ghent, Belgium. , (Belgium)
  • 5 Department of Electronics and Information Systems, Ghent University, Ghent, Belgium. , (Belgium)
  • 6 Department of Morphology, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium. , (Belgium)
  • 7 Applied Veterinary Morphology, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium. , (Belgium)
Published Article
Wiley (John Wiley & Sons)
Publication Date
Mar 01, 2019
DOI: 10.1002/hep.30294
PMID: 30259536


Angiogenesis contributes to the development of nonalcoholic steatohepatitis (NASH) and promotes inflammation, fibrosis, and progression to hepatocellular carcinoma (HCC). Angiopoietin-2 (Ang-2) is a key regulator of angiogenesis. We aimed to investigate the role of Ang-2 and its potential as a therapeutic target in NASH using human samples, in vivo mouse models, and in vitro assays. Serum Ang-2 levels were determined in 104 obese patients undergoing bariatric surgery and concomitant liver biopsy. The effect of the Ang-2/Tie2 receptor inhibiting peptibody L1-10 was evaluated in the methionine-choline deficient (MCD) and streptozotocin-western diet nonalcoholic fatty liver disease mouse models, and in vitro on endothelial cells and bone marrow-derived macrophages. The hepatic vasculature was visualized with µCT scans and scanning electron microscopy of vascular casts. Serum Ang-2 levels were increased in patients with histological NASH compared with patients with simple steatosis and correlated with hepatic CD34 immunoreactivity as a marker of hepatic angiogenesis. Serum and hepatic Ang-2 levels were similarly increased in mice with steatohepatitis. Both preventive and therapeutic L1-10 treatment reduced hepatocyte ballooning and fibrosis in MCD diet-fed mice and was associated with reduced hepatic angiogenesis and normalization of the vascular micro-architecture. Liver-isolated endothelial cells and monocytes from MCD-fed L1-10-treated mice showed reduced expression of leukocyte adhesion and inflammatory markers, respectively, compared with cells from untreated MCD diet-fed mice. In the streptozotocin-western diet model, therapeutic Ang-2 inhibition was able to reverse NASH and attenuate HCC progression. In vitro, L1-10 treatment mitigated increased cytokine production in lipopolysaccharide-stimulated endothelial cells but not in macrophages. Conclusion: Our findings provide evidence for Ang-2 inhibition as a therapeutic strategy to target pathological angiogenesis in NASH. © 2018 by the American Association for the Study of Liver Diseases.

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