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Article

Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction

1
Laboratory of Nutrient Sensing & Adipocyte Signaling, 6400 Perkins Road, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
2
Laboratory of Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
3
Program in Cardiovascular and Metabolic Disorders and Center for Computational Biology, Duke-NUS Medical School, Singapore 169857, Singapore
4
Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 7000 Fannin St, Houston, TX 77030, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Lynnette Ferguson and Ahmed El-Sohemy
Nutrients 2021, 13(6), 1788; https://doi.org/10.3390/nu13061788
Received: 12 April 2021 / Revised: 13 May 2021 / Accepted: 20 May 2021 / Published: 24 May 2021
(This article belongs to the Special Issue Nutrigenomics and the Future of Nutrition)
The principal sensing of dietary methionine restriction (MR) occurs in the liver, where it activates multiple transcriptional programs that mediate various biological components of the response. Hepatic Fgf21 is a key target and essential endocrine mediator of the metabolic phenotype produced by dietary MR. The transcription factor, Nfe2l2, is also activated by MR and functions in tandem with hepatic Atf4 to transactivate multiple, antioxidative components of the integrated stress response. However, it is unclear whether the transcriptional responses linked to Nfe2l2 activation by dietary MR are essential to the biological efficacy of the diet. Using mice with liver-specific deletion of Nfe2l2 (Nfe2l2fl/(Alb)) and their floxed littermates (Nfe2l2fl/fl) fed either Control or MR diets, the absence of hepatic Nfe2l2 had no effect on the ability of the MR diet to increase FGF21, reduce body weight and adiposity, and increase energy expenditure. Moreover, the primary elements of the hepatic transcriptome were similarly affected by MR in both genotypes, with the only major differences occurring in induction of the P450-associated drug metabolism pathway and the pentose glucuronate interconversion pathway. The biological significance of these pathways is uncertain but we conclude that hepatic Nfe2l2 is not essential in mediating the metabolic effects of dietary MR. View Full-Text
Keywords: essential amino acid; nutrient sensing; obesity; integrated stress response; Nfe2l2; FGF21 essential amino acid; nutrient sensing; obesity; integrated stress response; Nfe2l2; FGF21
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MDPI and ACS Style

Fang, H.; Stone, K.P.; Ghosh, S.; Forney, L.A.; Sims, L.C.; Vincik, L.; Gettys, T.W. Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction. Nutrients 2021, 13, 1788. https://doi.org/10.3390/nu13061788

AMA Style

Fang H, Stone KP, Ghosh S, Forney LA, Sims LC, Vincik L, Gettys TW. Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction. Nutrients. 2021; 13(6):1788. https://doi.org/10.3390/nu13061788

Chicago/Turabian Style

Fang, Han, Kirsten P. Stone, Sujoy Ghosh, Laura A. Forney, Landon C. Sims, LeighAnn Vincik, and Thomas W. Gettys 2021. "Hepatic Nfe2l2 Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction" Nutrients 13, no. 6: 1788. https://doi.org/10.3390/nu13061788

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