Abstract | BACKGROUND: METHODS: Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep) were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2) or normoxia (16% O2) for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking. RESULTS: Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03), which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia. CONCLUSIONS: Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver tissue hypoxia in hepatic steatosis. HIF-1 is necessary for collagen cross-linking in an in vitro model of fibrosis.
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Authors | Omar A Mesarwi, Mi-Kyung Shin, Shannon Bevans-Fonti, Christina Schlesinger, Janet Shaw, Vsevolod Y Polotsky |
Journal | PloS one
(PLoS One)
Vol. 11
Issue 12
Pg. e0168572
( 2016)
ISSN: 1932-6203 [Electronic] United States |
PMID | 28030556
(Publication Type: Journal Article)
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Chemical References |
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
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Topics |
- Animals
- Cells, Cultured
- Disease Models, Animal
- Hepatocytes
(metabolism, pathology)
- Hypoxia
(etiology, metabolism, pathology)
- Hypoxia-Inducible Factor 1, alpha Subunit
(physiology)
- Liver Cirrhosis
(etiology, metabolism, pathology)
- Male
- Mice
- Mice, Knockout
- Non-alcoholic Fatty Liver Disease
(complications, physiopathology)
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