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CRISPR Cas9-mediated deletion of biliverdin reductase A (BVRA) in mouse liver cells induces oxidative stress and lipid accumulation
- Source :
- Arch Biochem Biophys
- Publication Year :
- 2019
-
Abstract
- Obesity is the predominant cause of non-alcoholic fatty liver disease (NAFLD), which is associated with insulin resistance and diabetes. NAFLD includes a spectrum of pathologies that starts with simple steatosis, which can progress to non-alcoholic steatohepatitis (NASH) with the commission of other factors such as the enhancement of reactive oxygen species (ROS). Biliverdin reductase A (BVRA) reduces biliverdin to the antioxidant bilirubin, which may serve to prevent NAFLD, and possibly the progression to NASH. To further understand the role of BVRA in hepatic function, we used CRISPR-Cas9 technology to target the Blvra gene in the murine hepa1c1c7 hepatocyte cell line (BVRA KO). BVRA activity and protein levels were significantly lower in BVRA KO vs. wild-type (WT) hepatocytes. Lipid accumulation under basal and serum-starved conditions was significantly (p 0.05) higher in BVRA KO vs. WT cells. The loss of BVRA resulted in the reduction of mitochondria number, decreased expression of markers of mitochondrial biogenesis, uncoupling, oxidation, and fusion, which paralleled reduced mitochondrial oxygen consumption. BVRA KO cells exhibited increased levels of ROS generation and decreased levels of superoxide dismutase mRNA expression. In conclusion, our data demonstrate a critical role for BVRA in protecting against lipid accumulation and oxidative stress in hepatocytes, which may serve as a future therapeutic target for NAFLD and its progression to NASH.
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
Oxidoreductases Acting on CH-CH Group Donors
Bilirubin
Biophysics
medicine.disease_cause
Biochemistry
Article
Cell Line
Lipid peroxidation
03 medical and health sciences
chemistry.chemical_compound
Gene Knockout Techniques
Mice
Internal medicine
CRISPR-Associated Protein 9
medicine
Animals
Molecular Biology
Biliverdin
030102 biochemistry & molecular biology
Biliverdin reductase
Fatty liver
nutritional and metabolic diseases
medicine.disease
Lipid Metabolism
digestive system diseases
Oxidative Stress
030104 developmental biology
Endocrinology
chemistry
Hepatocytes
Steatosis
Steatohepatitis
CRISPR-Cas Systems
Reactive Oxygen Species
Oxidative stress
Gene Deletion
Subjects
Details
- ISSN :
- 10960384
- Volume :
- 672
- Database :
- OpenAIRE
- Journal :
- Archives of biochemistry and biophysics
- Accession number :
- edsair.doi.dedup.....b710c48ed09422d00f012d9583a2a01e