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Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis

Stress is a risk factor for several cardiovascular pathologies. PPARα holds a fundamental role in control of lipid homeostasis by directly regulating genes involved in fatty acid transport and oxidation. Importantly, PPARα agonists are effective in raising HDL-cholesterol and lowering triglycerides,...

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Autores principales: Konstandi, Maria, Shah, Yatrik M., Matsubara, Tsutomu, Gonzalez, Frank J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743822/
https://www.ncbi.nlm.nih.gov/pubmed/23967086
http://dx.doi.org/10.1371/journal.pone.0070675
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author Konstandi, Maria
Shah, Yatrik M.
Matsubara, Tsutomu
Gonzalez, Frank J.
author_facet Konstandi, Maria
Shah, Yatrik M.
Matsubara, Tsutomu
Gonzalez, Frank J.
author_sort Konstandi, Maria
collection PubMed
description Stress is a risk factor for several cardiovascular pathologies. PPARα holds a fundamental role in control of lipid homeostasis by directly regulating genes involved in fatty acid transport and oxidation. Importantly, PPARα agonists are effective in raising HDL-cholesterol and lowering triglycerides, properties that reduce the risk for cardiovascular diseases. This study investigated the role of stress and adrenergic receptor (AR)-related pathways in PPARα and HNF4α regulation and signaling in mice following repeated restraint stress or treatment with AR-antagonists administered prior to stress to block AR-linked pathways. Repeated restraint stress up-regulated Pparα and its target genes in the liver, including Acox, Acot1, Acot4, Cyp4a10, Cyp4a14 and Lipin2, an effect that was highly correlated with Hnf4α. In vitro studies using primary hepatocyte cultures treated with epinephrine or AR-agonists confirmed that hepatic AR/cAMP/PKA/CREB- and JNK-linked pathways are involved in PPARα and HNF4α regulation. Notably, restraint stress, independent of PPARα, suppressed plasma triglyceride levels. This stress-induced effect could be attributed in part to hormone sensitive lipase activation in the white adipose tissue, which was not prevented by the increased levels of perilipin. Overall, this study identifies a mechanistic basis for the modification of lipid homeostasis following stress and potentially indicates novel roles for PPARα and HNF4α in stress-induced lipid metabolism.
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spelling pubmed-37438222013-08-21 Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis Konstandi, Maria Shah, Yatrik M. Matsubara, Tsutomu Gonzalez, Frank J. PLoS One Research Article Stress is a risk factor for several cardiovascular pathologies. PPARα holds a fundamental role in control of lipid homeostasis by directly regulating genes involved in fatty acid transport and oxidation. Importantly, PPARα agonists are effective in raising HDL-cholesterol and lowering triglycerides, properties that reduce the risk for cardiovascular diseases. This study investigated the role of stress and adrenergic receptor (AR)-related pathways in PPARα and HNF4α regulation and signaling in mice following repeated restraint stress or treatment with AR-antagonists administered prior to stress to block AR-linked pathways. Repeated restraint stress up-regulated Pparα and its target genes in the liver, including Acox, Acot1, Acot4, Cyp4a10, Cyp4a14 and Lipin2, an effect that was highly correlated with Hnf4α. In vitro studies using primary hepatocyte cultures treated with epinephrine or AR-agonists confirmed that hepatic AR/cAMP/PKA/CREB- and JNK-linked pathways are involved in PPARα and HNF4α regulation. Notably, restraint stress, independent of PPARα, suppressed plasma triglyceride levels. This stress-induced effect could be attributed in part to hormone sensitive lipase activation in the white adipose tissue, which was not prevented by the increased levels of perilipin. Overall, this study identifies a mechanistic basis for the modification of lipid homeostasis following stress and potentially indicates novel roles for PPARα and HNF4α in stress-induced lipid metabolism. Public Library of Science 2013-08-14 /pmc/articles/PMC3743822/ /pubmed/23967086 http://dx.doi.org/10.1371/journal.pone.0070675 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.
spellingShingle Research Article
Konstandi, Maria
Shah, Yatrik M.
Matsubara, Tsutomu
Gonzalez, Frank J.
Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis
title Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis
title_full Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis
title_fullStr Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis
title_full_unstemmed Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis
title_short Role of PPARα and HNF4α in Stress-Mediated Alterations in Lipid Homeostasis
title_sort role of pparα and hnf4α in stress-mediated alterations in lipid homeostasis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3743822/
https://www.ncbi.nlm.nih.gov/pubmed/23967086
http://dx.doi.org/10.1371/journal.pone.0070675
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