This is an author version of the contribution published on:
Questa è la versione dell’autore dell’opera:
[Journal of Hepatology, Vol. 66, 2017]
ovvero [E. Morello, S. Sutti, B. Foglia, S. Cannito, E. Novo, C. Bocca, S. Bruzzi, E.
Bugianesi, E. Albano, M. Parola
Vol.66, 2017, pagg.S169-S170]
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searchType=quick&searchText=international+liver+congress&occurrences=all&journ
alCode=jhepat&searchScope=fullSite]
Hypoxia-inducible factor 2alpha drives the progression of experimental non-alcoholic fatty liver disease by stimulating hepatocyte production of histidine rich glycoprotein
E. Morello1, S. Sutti2, B. Foglia1, S. Cannito1, E. Novo1, C. Bocca1, S. Bruzzi3, E. Bugianesi2, E. Albano3, M. Parola1
1Dept. Clinical and Biological Sciences; 2Dept. Medical Sciences, University of Torino, Torino; 3Dep. Health Sciences, A. Avogadro University, Novara, Italy E-mail: maurizio.parola@unito.it
Background and Aims: Hypoxia and hypoxia inducible factors (HIFs) are believed to significantly affect fibrogenic progression of chronic liver diseases (CLD). Recently, we showed that HIF-2alpha expression is up-regulated in parenchymal cells in either experimental or human non-alcoholic fatty liver disease (NAFLD) and contributes in sustaining liver fibrogenesis in the methionine/choline-deficient (MCD) diet model of NAFLD. In the present study, we provide further insides in the mechanisms by which HIF-2alpha promotes the progression of experimental NAFLD.
Methods: NAFLD was induced by feeding mice with hepatocytespecific conditional deletion of HIF-2alpha (HIF-2alpha fl/fl/Alb-Cre mice) and control littermates with MCD and choline-deficient Lamino acid refined (CDAA) diets. In vitro studies have been performed using HepG2 cells
overexpressing HIF-2alpha.
Results: In both the dietary models of NAFLD hepatocyte deletion
of HIF-2 alpha resulted in: (i) a decrease in fatty liver and parenchymal necrosis; (ii) amelioration in lobular inflammation and in the hepatic expression of pro-inflammatory cyto/chemokines (TNF, IL-12, CCL2, CXCL10); (iii) a significant decrease in the expression of pro-fibrogenic genes (collagen 1A1, TGF-beta1, alphaSMA) as well as in extracellular matrix deposition (Sirius Red staining) and in the number of activated myofibroblasts. Such an improvement in NAFLD evolution in HIF-2α deficient mice was associated with a selective lowering of the hepatic production of Histidine-Rich Glycoprotein (HRGP), a hepatocyte-derived protein recently implicated in sustaining macrophage M1 activation. Accordingly, flow cytometry showed a decreased production of IL-12 by
macrophages isolated from HIF-2alpha fl/fl/Alb-Cre mice receiving the MCD diet. Furthermore, in vitro experiments confirmed that up-regulation of HIF-2alpha resulted in enhanced HRGP
expression by HepG2 cells.
Conclusions: These results indicate that activation of HIF-2alpha in hepatocytes stimulates the progression of experimental NAFLD through the up-regulation of HRGP production.