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Nuclear factor‐erythroid 2‐related factor 1 regulates expression of proteasome genes in hepatocytes and protects against endoplasmic reticulum stress and steatosis in mice
Author(s) -
Lee Candy S.,
Ho Daniel V.,
Chan Jefferson Y.
Publication year - 2013
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.12350
Subject(s) - nrf1 , endoplasmic reticulum , proteasome , microbiology and biotechnology , unfolded protein response , steatosis , biology , transcription factor , endoplasmic reticulum associated protein degradation , endocrinology , biochemistry , gene
The ubiquitin–proteasome system is important in maintaining protein homeostasis. NFE 2‐related factor 1 (Nrf1), a transcription factor in the cap ‘n’ collar basic‐leucine zipper family, regulates expression of cytoprotective genes. It was previously shown that liver‐specific knockout of Nrf1 (Nrf1 LKO ) leads to hepatic cell death, steatohepatitis and cancer. However, the mechanisms underlying these pathologies are not clear. Here, we report that Nrf1 is critical for proteasome gene expression in the liver. Liver‐specific knockout of Nrf1 results in impaired basal and induced expression of proteasome genes, and diminished proteasome activity in hepatocytes. In addition, our findings demonstrated that endoplasmic reticulum stress signaling pathway was also activated in Nrf1 LKO livers. Inhibition of proteasome activity leads to endoplasmic reticulum stress in Nrf1‐deficient hepatocytes, prompting the development of steatosis in the liver. Our results indicate that Nrf1 plays an integral role in the maintenance of proteasome function in hepatocytes and in the prevention of liver steatosis development. Moreover, these results highlight an association between proteasome dysfunction, endoplasmic reticulum stress and steatosis.