These authors share senior authorship.
Steatohepatitis/Metabolic Liver Disease
Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice
Article first published online: 12 MAY 2014
© 2014 The Authors. Hepatology published by Wiley on behalf of the American Association for the Study of Liver Diseases.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Volume 60, Issue 2, pages 531–544, August 2014
How to Cite
Locatelli, I., Sutti, S., Jindal, A., Vacchiano, M., Bozzola, C., Reutelingsperger, C., Kusters, D., Bena, S., Parola, M., Paternostro, C., Bugianesi, E., McArthur, S., Albano, E. and Perretti, M. (2014), Endogenous annexin A1 is a novel protective determinant in nonalcoholic steatohepatitis in mice. Hepatology, 60: 531–544. doi: 10.1002/hep.27141
Potential conflict of interest: Nothing to report.
This work has been supported by grants from the Fondazione Cariplo, Milan, Italy (grant no.: 2011-0470), The Wellcome Trust (Programme 086867/Z/08/Z) and, in part, The William Harvey Research Foundation (London, UK). I.L. Ph.D. training at the Scuola di Alta Formazione of the University of East Piendmont was supported by the Compagnia di San Paolo (Turin, Italy) and partially by the Fondazione Cariplo (NutriAl Network 2010).
- Issue published online: 22 JUL 2014
- Article first published online: 12 MAY 2014
- Accepted manuscript online: 25 MAR 2014 04:30AM EST
- Manuscript Accepted: 19 MAR 2014
- Manuscript Revised: 3 MAR 2014
- Manuscript Received: 23 JAN 2014
Annexin A1 (AnxA1) is an effector of the resolution of inflammation and is highly effective in terminating acute inflammatory responses. However, its role in chronic settings is less investigated. Because changes in AnxA1 expression within adipose tissue characterize obesity in mice and humans, we queried a possible role for AnxA1 in the pathogenesis of nonalcoholic steatohepatitis (NASH), a disease commonly associated with obesity. NASH was induced in wild-type (WT) and AnxA1 knockout (AnxA1 KO) C57BL/6 mice by feeding a methionine-choline deficient (MCD) diet up to 8 weeks. In MCD-fed WT mice, hepatic AnxA1 increased in parallel with progression of liver injury. This mediator was also detected in liver biopsies from patients with NASH and its degree of expression inversely correlated with the extent of fibrosis. In both humans and rodents, AnxA1 production was selectively localized in liver macrophages. NASH in AnxA1 KO mice was characterized by enhanced lobular inflammation resulting from increased macrophage recruitment and exacerbation of the M1 phenotype. Consistently, in vitro addition of recombinant AnxA1 to macrophages isolated from NASH livers down-modulated M1 polarization through stimulation of interleukin-10 production. Furthermore, the degree of hepatic fibrosis was enhanced in MCD-fed AnxA1 KO mice, an effect associated with augmented liver production of the profibrotic lectin, galectin-3. Accordingly, AnxA1 addition to isolated hepatic macrophages reduced galectin-3 expression. Conclusions: Macrophage-derived AnxA1 plays a functional role in modulating hepatic inflammation and fibrogenesis during NASH progression, suggesting the possible use of AnxA1 analogs for therapeutic control of this disease. (Hepatology 2014;60:531–544)