Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction
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 <i>Fgf21</i> is a key target and essential endocrine mediator of the metabolic phenot...
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| Format: | Article |
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MDPI AG
2021-05-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/13/6/1788 |
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| author | Han Fang Kirsten P. Stone Sujoy Ghosh Laura A. Forney Landon C. Sims LeighAnn Vincik Thomas W. Gettys |
| author_facet | Han Fang Kirsten P. Stone Sujoy Ghosh Laura A. Forney Landon C. Sims LeighAnn Vincik Thomas W. Gettys |
| author_sort | Han Fang |
| collection | DOAJ |
| description | 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 <i>Fgf21</i> is a key target and essential endocrine mediator of the metabolic phenotype produced by dietary MR. The transcription factor, <i>Nfe2l2</i>, is also activated by MR and functions in tandem with hepatic <i>Atf4</i> to transactivate multiple, antioxidative components of the integrated stress response. However, it is unclear whether the transcriptional responses linked to <i>Nfe2l2</i> activation by dietary MR are essential to the biological efficacy of the diet. Using mice with liver-specific deletion of <i>Nfe2l2</i> (<i>Nfe2l2</i><sup>fl/(Alb)</sup>) and their floxed littermates (<i>Nfe2l2</i><sup>fl/fl</sup>) fed either Control or MR diets, the absence of hepatic <i>Nfe2l2</i> 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 <i>Nfe2l2</i> is not essential in mediating the metabolic effects of dietary MR. |
| first_indexed | 2024-03-10T11:06:22Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-10T11:06:22Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
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| series | Nutrients |
| spelling | doaj.art-6397789e3b434fa3b7e9e3e0c5437e1a2023-11-21T21:07:19ZengMDPI AGNutrients2072-66432021-05-01136178810.3390/nu13061788Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine RestrictionHan Fang0Kirsten P. Stone1Sujoy Ghosh2Laura A. Forney3Landon C. Sims4LeighAnn Vincik5Thomas W. Gettys6Laboratory of Nutrient Sensing & Adipocyte Signaling, 6400 Perkins Road, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USALaboratory of Nutrient Sensing & Adipocyte Signaling, 6400 Perkins Road, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USALaboratory of Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USADepartment of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, 7000 Fannin St, Houston, TX 77030, USALaboratory of Nutrient Sensing & Adipocyte Signaling, 6400 Perkins Road, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USALaboratory of Nutrient Sensing & Adipocyte Signaling, 6400 Perkins Road, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USALaboratory of Nutrient Sensing & Adipocyte Signaling, 6400 Perkins Road, Pennington Biomedical Research Center, Baton Rouge, LA 70808, USAThe 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 <i>Fgf21</i> is a key target and essential endocrine mediator of the metabolic phenotype produced by dietary MR. The transcription factor, <i>Nfe2l2</i>, is also activated by MR and functions in tandem with hepatic <i>Atf4</i> to transactivate multiple, antioxidative components of the integrated stress response. However, it is unclear whether the transcriptional responses linked to <i>Nfe2l2</i> activation by dietary MR are essential to the biological efficacy of the diet. Using mice with liver-specific deletion of <i>Nfe2l2</i> (<i>Nfe2l2</i><sup>fl/(Alb)</sup>) and their floxed littermates (<i>Nfe2l2</i><sup>fl/fl</sup>) fed either Control or MR diets, the absence of hepatic <i>Nfe2l2</i> 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 <i>Nfe2l2</i> is not essential in mediating the metabolic effects of dietary MR.https://www.mdpi.com/2072-6643/13/6/1788essential amino acidnutrient sensingobesityintegrated stress responseNfe2l2FGF21 |
| spellingShingle | Han Fang Kirsten P. Stone Sujoy Ghosh Laura A. Forney Landon C. Sims LeighAnn Vincik Thomas W. Gettys Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction Nutrients essential amino acid nutrient sensing obesity integrated stress response Nfe2l2 FGF21 |
| title | Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction |
| title_full | Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction |
| title_fullStr | Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction |
| title_full_unstemmed | Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction |
| title_short | Hepatic <i>Nfe2l2</i> Is Not an Essential Mediator of the Metabolic Phenotype Produced by Dietary Methionine Restriction |
| title_sort | hepatic i nfe2l2 i is not an essential mediator of the metabolic phenotype produced by dietary methionine restriction |
| topic | essential amino acid nutrient sensing obesity integrated stress response Nfe2l2 FGF21 |
| url | https://www.mdpi.com/2072-6643/13/6/1788 |
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