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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06706-11.

ACKNOWLEDGMENTS

We thank S. Sato, M. Ohtsuji, and G. Ishikawa for their help. We thank E. Naganuma and Y. Kawatani for assistance with the microarray analysis and the Biomedical Research Core of Tohoku University Graduate School of Medicine for technical support.

This study was supported in part by Grants-in-Aid for Creative Scientific Research (to M.Y.), for Scientific Research on Priority Areas (to M.Y.), for Scientific Research (to F.K. and M.Y.), and for Exploratory Research (to M.Y.) from the Ministry of Education, Science, Sports and Culture. This work was also supported by grants from the JST-ERATO project (to M.Y.), Naito Foundation (to M.Y.), Tohoku University Global COE Program for the Conquest of Diseases with Network Medicine (to M.Y.), and Mochida Pharmaceutical Co., Ltd. (to M.Y.).