Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 672, Issue -, Pages -Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2019.108072
Keywords
Bilirubin; Hepatocytes; Lipid peroxidation; Mitochondria; Reactive oxygen species; Obesity; Steatosis
Categories
Funding
- CEPR COBRE [P20GM121334]
- National Heart, Lung and Blood Institute [K01HL-125445, PO1HL-051971, 1T32HL105324]
- National Institute of General Medical Sciences [P20GM104357-02]
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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. wildtype (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.
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