The role of iNOS in cholesterol-induced liver fibrosis

Sarit Anavi, Michal Eisenberg-Bord, Michal Hahn-Obercyger, Olga Genin, Mark Pines, Oren Tirosh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

56 Scopus citations


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.

Original languageAmerican English
Pages (from-to)914-924
Number of pages11
JournalLaboratory Investigation
Issue number8
StatePublished - 30 Aug 2015

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