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-1␤ (for peroxisome proliferator-activated receptor ␥ coactivator 1␤). Chromatin immunoprecipitation analyses showed that Nrf1 binds to the antioxidant response elements (AREs) in regulatory regions of the Lipin1 and PGC-1␤ 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-1␤ genes, providing new insights into the Nrf1 function in hepatic lipid metabolism.

mTORC1 signaling activates NRF1 to increase cellular proteasome levels

“…Finally, it is worth noting that liver-specific deletion of Nfe2l1 in mice disrupts lipid homeostasis, resulting in hepatic lipid accumulation, and NRF1 has been proposed to control the expression of a subset of enzymes involved in lipid metabolism. 38,40,41 These findings suggest additional underlying functions of NRF1 that might also account for its control by SREBP1.…”

Small Maf proteins (MafF, MafG, MafK): History, structure and function

“…However, because MafG −/− ::MafK −/− mice die before weaning (Onodera et al, 2000), this phenotype has not been confirmed in sMaf knockouts. Nrf1 knockout mouse studies have suggested that Nrf1 regulates genes involved in various metabolic pathways, such as fatty acid and amino acid metabolism, as well as proteasome subunit genes (Hirotsu et al, 2012a). These genes are thought to be regulated by Nrf1-sMaf heterodimers, and further studies, such as sMaf conditional targeting analyses, are expected to support this hypothesis.…”

How lipid droplets “TAG” along: Glycerolipid synthetic enzymes and lipid storage

“…Hepatocyte nuclear factor 4α (HNF4α) also cooperates with PGC-1α to regulate Lpin1 expression in liver cells [151]. The regulation of Lpin1 by NF-E2-related factor 1 (Nrf1) occurs through binding to antioxidant response elements (AREs) [152]. Ethanol increases Lpin1 gene expression, which is mediated through inhibition of AMPK and activation of SREBP-1 [153].…”