Transcription factor Nrf1 negatively regulates the cystine/glutamate transporter and lipid-metabolizing enzymes

Mol Cell Biol. 2014 Oct;34(20):3800-16. doi: 10.1128/MCB.00110-14. Epub 2014 Aug 4.

Abstract

Liver-specific Nrf1 (NF-E2-p45-related factor 1) knockout mice develop nonalcoholic steatohepatitis. To identify postnatal mechanisms responsible for this phenotype, we generated an inducible liver-specific Nrf1 knockout mouse line using animals harboring an Nrf1(flox) allele and a rat CYP1A1-Cre transgene (Nrf1(flox/flox)::CYP1A1-Cre mice). Administration of 3-methylcholanthrene (3-MC) to these mice (Nrf1(flox/flox)::CYP1A1-Cre+3MC mice) resulted in loss of hepatic Nrf1 expression. The livers of mice lacking Nrf1 accumulated lipid, and the hepatic fatty acid (FA) composition in such animals differed significantly from that in the Nrf1(flox/flox)::CYP1A1-Cre control. This change was provoked by upregulation of several FA metabolism genes. Unexpectedly, we also found that the level of glutathione was increased dramatically in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice. While expression of glutathione biosynthetic enzymes was unchanged, xCT, a component of the cystine/glutamate antiporter system x(c)(-), was significantly upregulated in livers of Nrf1(flox/flox)::CYP1A1-Cre+3MC mice, suggesting that Nrf1 normally suppresses xCT. Thus, stress-inducible expression of xCT is a two-step process: under homeostatic conditions, Nrf1 effectively suppresses nonspecific transactivation of xCT, but when cells encounter severe oxidative/electrophilic stress, Nrf1 is displaced from an antioxidant response element (ARE) in the gene promoter while Nrf2 is recruited to the ARE. Thus, Nrf1 controls both the FA and the cystine/cysteine content of hepatocytes by participating in an elaborate regulatory network.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport System y+ / genetics
  • Amino Acid Transport System y+ / metabolism
  • Amino Acid Transport Systems, Acidic / genetics
  • Amino Acid Transport Systems, Acidic / metabolism*
  • Animals
  • Cell Line
  • Cystine / metabolism
  • Cytochrome P-450 CYP1A1 / genetics
  • Fatty Acid Desaturases / genetics*
  • Fatty Acid Desaturases / metabolism
  • Female
  • Gene Expression Regulation, Enzymologic*
  • Glutathione / metabolism
  • Hepatocytes / metabolism
  • LDL-Receptor Related Proteins / genetics
  • LDL-Receptor Related Proteins / metabolism
  • Lipid Metabolism*
  • Liver / cytology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Respiratory Factor 1 / physiology*
  • Protein Binding
  • Rats
  • Receptors, Lipoprotein / genetics
  • Receptors, Lipoprotein / metabolism
  • Response Elements
  • Transcriptional Activation
  • Triglycerides / metabolism

Substances

  • Amino Acid Transport System y+
  • Amino Acid Transport Systems, Acidic
  • LDL-Receptor Related Proteins
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Receptors, Lipoprotein
  • Slc7a11 protein, mouse
  • Triglycerides
  • xCT protein, rat
  • Cystine
  • Cytochrome P-450 CYP1A1
  • Fatty Acid Desaturases
  • Glutathione