title: NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid metabolism through regulation of the Lipin1 and PGC-1β genes.
abstract: Hepatic lipid metabolism is under elaborate regulation, and perturbations in this regulatory process at the transcriptional level lead to pathological conditions. NF-E2-related factor 1 (Nrf1) is a member of the cap'n'collar (CNC) transcription factor family. Hepatocyte-specific Nrf1 gene conditional-knockout mice are known to develop hepatic steatosis, but it remains unclear how Nrf1 contributes to the lipid homeostasis. Therefore, in this study we examined the gene expression profiles of Nrf1-deficient mouse livers. A pathway analysis based on the profiling results revealed that the levels of expression of the genes related to lipid metabolism, amino acid metabolism, and mitochondrial respiratory function were decreased in Nrf1-deficient mouse livers, indicating the profound effects that the Nrf1 deficiency conferred to various metabolic pathways. We discovered that the Nrf1 deficiency leads to the reduced expression of the transcriptional coactivator genes Lipin1 and PGC-1β (for peroxisome proliferator-activated receptor γ coactivator 1β). Chromatin immunoprecipitation analyses showed that Nrf1 binds to the antioxidant response elements (AREs) in regulatory regions of the Lipin1 and PGC-1β genes and the binding of Nrf1 to the AREs activates reporter gene transcription. These results thus identified Nrf1 to be a novel regulator of the Lipin1 and PGC-1β genes, providing new insights into the Nrf1 function in hepatic lipid metabolism.
authors.affiliation: Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Hirotsu
authors.forename: Nami
authors.initials: N
authors.lastname: Hataya
authors.forename: Fumiki
authors.initials: F
authors.lastname: Katsuoka
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000378:metabolism*; D053858:Metabolic Networks and Pathways / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051265:NF-E2-Related Factor 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000235:genetics; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase / Q000235:genetics*; D011401:Promoter Regions, Genetic; D051257:Proto-Oncogene Proteins c-maf / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors
chemical_list: D017931:DNA Primers; C495608:Maf protein, mouse; D051265:NF-E2-Related Factor 1; C093714:Nfe2L1 protein, mouse; D009687:Nuclear Proteins; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D051257:Proto-Oncogene Proteins c-maf; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase