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Mechanism for HIF-1 activation by cholesterol under normoxia: A redox signaling pathway for liver damage
- Source :
- Free Radical Biology and Medicine. 71:61-69
- Publication Year :
- 2014
- Publisher :
- Elsevier BV, 2014.
-
Abstract
- Cholesterol and chronic activation of hypoxia-inducible factor-1 (HIF-1) have been separately implicated in the pathogenesis and progression of liver diseases. In AML12 hepatocytes increased HIF-1α protein accumulation was evident after 2 h of incubation with cholesterol, whereas enhanced HIF-1 transcriptional activity was observed after 6 h. Investigations into the molecular mechanism have shown that cholesterol inhibited HIF-1α degradation. Mitochondrial dysfunction and enhanced mitochondrial reactive oxygen species (ROS) generation were observed in 2-h cholesterol-treated cells along with augmented nitric oxide (NO) levels. Further analysis indicated that HIF-1α stabilization at later time (6h), but not after 2h, of incubation with cholesterol was dependent on NO production. To elucidate the role of mitochondrial dysfunction in HIF-1α stabilization, mitochondrial DNA-depleted hepatocytes were prepared. In these cells the ability of cholesterol to activate the HIF-1 pathway was abolished. Similarly, catalase overexpression also attenuated cholesterol-induced HIF-1α accumulation. These results demonstrate that cholesterol promotes HIF-1 activation in a ROS- and NO-dependent manner. Chronic liver activation of HIF-1 by cholesterol may mediate its deleterious effects in the liver.
- Subjects :
- medicine.medical_specialty
Transcription, Genetic
Inflammation
Biology
Nitric Oxide
medicine.disease_cause
DNA, Mitochondrial
Biochemistry
Cell Line
Nitric oxide
Pathogenesis
Mice
chemistry.chemical_compound
Physiology (medical)
Internal medicine
medicine
Animals
Liver X receptor
chemistry.chemical_classification
Reactive oxygen species
Cholesterol
Catalase
Hypoxia-Inducible Factor 1, alpha Subunit
Mitochondria
Endocrinology
Gene Expression Regulation
chemistry
Proteolysis
Hepatocytes
biology.protein
medicine.symptom
Reactive Oxygen Species
Oxidation-Reduction
Oxidative stress
Signal Transduction
Subjects
Details
- ISSN :
- 08915849
- Volume :
- 71
- Database :
- OpenAIRE
- Journal :
- Free Radical Biology and Medicine
- Accession number :
- edsair.doi.dedup.....d1be633b5a3190181c226f0ca2334777