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Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression
OBJECTIVE: The peroxisome proliferator–activated receptor-γ coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1α show that this coactivator is impor...
Autores principales: | , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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American Diabetes Association
2009
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699879/ https://www.ncbi.nlm.nih.gov/pubmed/19366863 http://dx.doi.org/10.2337/db08-1571 |
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author | Estall, Jennifer L. Kahn, Mario Cooper, Marcus P. Fisher, ffolliott Martin Wu, Michele K. Laznik, Dina Qu, Lishu Cohen, David E. Shulman, Gerald I. Spiegelman, Bruce M. |
author_facet | Estall, Jennifer L. Kahn, Mario Cooper, Marcus P. Fisher, ffolliott Martin Wu, Michele K. Laznik, Dina Qu, Lishu Cohen, David E. Shulman, Gerald I. Spiegelman, Bruce M. |
author_sort | Estall, Jennifer L. |
collection | PubMed |
description | OBJECTIVE: The peroxisome proliferator–activated receptor-γ coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1α show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1α activity affect metabolism and energy homeostasis has yet to be determined. RESEARCH DESIGN AND METHODS: To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1α levels, we used the Cre/Lox system to create mice heterozygous for PGC-1α specifically within the liver (LH mice). RESULTS: These mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial β-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes. CONCLUSIONS: These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1α levels, underlining the importance of tightly regulated PGC-1α expression in the maintenance of lipid homeostasis and glucose metabolism. |
format | Text |
id | pubmed-2699879 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | American Diabetes Association |
record_format | MEDLINE/PubMed |
spelling | pubmed-26998792010-07-01 Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression Estall, Jennifer L. Kahn, Mario Cooper, Marcus P. Fisher, ffolliott Martin Wu, Michele K. Laznik, Dina Qu, Lishu Cohen, David E. Shulman, Gerald I. Spiegelman, Bruce M. Diabetes Original Article OBJECTIVE: The peroxisome proliferator–activated receptor-γ coactivator (PGC)-1 family of transcriptional coactivators controls hepatic function by modulating the expression of key metabolic enzymes. Hepatic gain of function and complete genetic ablation of PGC-1α show that this coactivator is important for activating the programs of gluconeogenesis, fatty acid oxidation, oxidative phosphorylation, and lipid secretion during times of nutrient deprivation. However, how moderate changes in PGC-1α activity affect metabolism and energy homeostasis has yet to be determined. RESEARCH DESIGN AND METHODS: To identify key metabolic pathways that may be physiologically relevant in the context of reduced hepatic PGC-1α levels, we used the Cre/Lox system to create mice heterozygous for PGC-1α specifically within the liver (LH mice). RESULTS: These mice showed fasting hepatic steatosis and diminished ketogenesis associated with decreased expression of genes involved in mitochondrial β-oxidation. LH mice also exhibited high circulating levels of triglyceride that correlated with increased expression of genes involved in triglyceride-rich lipoprotein assembly. Concomitant with defects in lipid metabolism, hepatic insulin resistance was observed both in LH mice fed a high-fat diet as well as in primary hepatocytes. CONCLUSIONS: These data highlight both the dose-dependent and long-term effects of reducing hepatic PGC-1α levels, underlining the importance of tightly regulated PGC-1α expression in the maintenance of lipid homeostasis and glucose metabolism. American Diabetes Association 2009-07 2009-04-14 /pmc/articles/PMC2699879/ /pubmed/19366863 http://dx.doi.org/10.2337/db08-1571 Text en © 2009 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details. |
spellingShingle | Original Article Estall, Jennifer L. Kahn, Mario Cooper, Marcus P. Fisher, ffolliott Martin Wu, Michele K. Laznik, Dina Qu, Lishu Cohen, David E. Shulman, Gerald I. Spiegelman, Bruce M. Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression |
title | Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression |
title_full | Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression |
title_fullStr | Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression |
title_full_unstemmed | Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression |
title_short | Sensitivity of Lipid Metabolism and Insulin Signaling to Genetic Alterations in Hepatic Peroxisome Proliferator–Activated Receptor-γ Coactivator-1α Expression |
title_sort | sensitivity of lipid metabolism and insulin signaling to genetic alterations in hepatic peroxisome proliferator–activated receptor-γ coactivator-1α expression |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699879/ https://www.ncbi.nlm.nih.gov/pubmed/19366863 http://dx.doi.org/10.2337/db08-1571 |
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