TY - JOUR
T1 - The role of iNOS in cholesterol-induced liver fibrosis
AU - Anavi, Sarit
AU - Eisenberg-Bord, Michal
AU - Hahn-Obercyger, Michal
AU - Genin, Olga
AU - Pines, Mark
AU - Tirosh, Oren
N1 - Publisher Copyright:
© 2015 USCAP, Inc All rights reserved.
PY - 2015/8/30
Y1 - 2015/8/30
N2 - Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1α stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis.
AB - Accumulation of cholesterol in the liver is associated with the development of non-alcoholic steatohepatitis-related fibrosis. However, underlying mechanisms are not well understood. The present study investigated the role of inducible nitric oxide synthase (iNOS) in cholesterol-induced liver fibrosis by feeding wild-type (WT) and iNOS-deficient mice with control or high-cholesterol diet (HCD) for 6 weeks. WT mice fed with HCD developed greater liver fibrosis, compared with iNOS-deficient mice, as evident by Sirius red staining and higher expression levels of profibrotic genes. Enhanced liver fibrosis in the presence of iNOS was associated with hypoxia-inducible factor-1α stabilization, matrix metalloproteinase-9 expression, and enhanced hepatic DNA damage. The profibrotic role of iNOS was also demonstrated in vivo using a selective inhibitor of iNOS as well as in vitro in a rat liver stellate cell line (HSC-T6). In conclusion, these findings suggest that iNOS is an important mediator in HCD-induced liver fibrosis.
UR - http://www.scopus.com/inward/record.url?scp=84938081206&partnerID=8YFLogxK
U2 - 10.1038/labinvest.2015.67
DO - 10.1038/labinvest.2015.67
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C2 - 26097999
AN - SCOPUS:84938081206
SN - 0023-6837
VL - 95
SP - 914
EP - 924
JO - Laboratory Investigation
JF - Laboratory Investigation
IS - 8
ER -