Abstract |
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.
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Authors | Sarit Anavi, Michal Eisenberg-Bord, Michal Hahn-Obercyger, Olga Genin, Mark Pines, Oren Tirosh |
Journal | Laboratory investigation; a journal of technical methods and pathology
(Lab Invest)
Vol. 95
Issue 8
Pg. 914-24
(Aug 2015)
ISSN: 1530-0307 [Electronic] United States |
PMID | 26097999
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
- Cholesterol
- Nitric Oxide Synthase Type II
- Matrix Metalloproteinase 9
- Mmp9 protein, mouse
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Topics |
- Animals
- Cell Line
- Cholesterol
(toxicity)
- DNA Damage
(drug effects, genetics)
- Diet, High-Fat
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Liver
(drug effects, pathology)
- Liver Cirrhosis
(chemically induced, metabolism)
- Male
- Matrix Metalloproteinase 9
(metabolism)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Nitric Oxide Synthase Type II
(genetics, metabolism)
- Rats
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