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NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid metabolism through regulation of the Lipin1 and PGC-1? 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.

SUBMITTER: Hirotsu Y

PROVIDER: S-EPMC3416188 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid metabolism through regulation of the Lipin1 and PGC-1β genes.

Hirotsu Yosuke Y Hataya Nami N Katsuoka Fumiki F Yamamoto Masayuki M

Molecular and cellular biology 20120514 14

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- ...[more]

PMID: 22586274

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Project description:Hepatic macroautophagy/autophagy and fatty acid metabolism are transcriptionally regulated by nuclear receptors (NRs); however, it is not known whether their transcriptional co-activators are involved in autophagy. We thus examined MED1 (mediator complex subunit 1), a key component of the Mediator Complex that directly interacts with NRs, on these processes. We found that MED1 knockdown (KD) in cultured hepatic cells decreased autophagy and mitochondrial activity that was accompanied by decreased transcription of genes involved in these processes. Lipophagy and fatty acid β-oxidation also were impaired. These effects also occurred after thyroid hormone stimulation, nutrient-replete or -deplete conditions, and in liver-specific Med1 KD (Med1 LKD) mice under fed and fasting conditions. Together, these findings showed that Med1 played a key role in hepatic autophagy, mitochondria function, and lipid metabolism under these conditions. Additionally, we identified downregulated hepatic genes in Med1 LKD mice, and subjected them to ChIP Enrichment Analysis. Our findings showed that the transcriptional activity of several NRs and transcription factors (TFs), including PPARA and FOXO1, likely were affected by Med1 LKD. Finally, Med1 expression and autophagy also were decreased in two mouse models of nonalcoholic fatty liver disease (NAFLD) suggesting that decreased Med1 may contribute to hepatosteatosis. In summary, MED1 plays an essential role in regulating hepatic autophagy and lipid oxidation during different hormonal and nutrient conditions. Thus, MED1 may serve as an integrator of multiple transcriptional pathways involved in these metabolic processes.Abbreviations: BAF: bafilomycin A1; db/db mice; Leprdb/db mice; ECAR: extracellular acidification rate; KD: knockdown; MED1: mediator complex subunit 1; NAFLD: nonalcoholic fatty liver disease; OCR: oxygen consumption rate; PPARA/PPARα: peroxisomal proliferator activated receptor alpha; TF: transcription factor; TFEB: transcription factor EB; tf-LC3: tandem fluorescence RFP-GFP-LC3; TG: triglyceride; TH: Thyroid hormone; TR: thyroid hormone receptors; V-ATPase: vacuolar-type H+-ATPase; WDF: Western diet with 15% fructose in drinking water.

Dataset Information

NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid metabolism through regulation of the Lipin1 and PGC-1? genes.

Publications

NF-E2-related factor 1 (Nrf1) serves as a novel regulator of hepatic lipid metabolism through regulation of the Lipin1 and PGC-1β genes.

Similar Datasets

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