CRISPR Cas9-mediated deletion of biliverdin reductase A (BVRA) in mouse liver cells induces oxidative stress and lipid accumulation

Darren M. Gordon, Samuel O. Adeosun, Somtochukwu I. Ngwudike, Christopher D. Anderson, John E. Hall, Terry D. Hinds, David E. Stec

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

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.

Original languageEnglish
Article number108072
JournalArchives of Biochemistry and Biophysics
Volume672
DOIs
StatePublished - Sep 15 2019

Bibliographical note

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

  • Bilirubin
  • Hepatocytes
  • Lipid peroxidation
  • Mitochondria
  • Obesity
  • Reactive oxygen species
  • Steatosis

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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