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Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity
Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. St...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162950/ https://www.ncbi.nlm.nih.gov/pubmed/32300166 http://dx.doi.org/10.1038/s41598-020-63579-3 |
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author | Régnier, Marion Polizzi, Arnaud Smati, Sarra Lukowicz, Céline Fougerat, Anne Lippi, Yannick Fouché, Edwin Lasserre, Frédéric Naylies, Claire Bétoulières, Colette Barquissau, Valentin Mouisel, Etienne Bertrand-Michel, Justine Batut, Aurélie Saati, Talal Al Canlet, Cécile Tremblay-Franco, Marie Ellero-Simatos, Sandrine Langin, Dominique Postic, Catherine Wahli, Walter Loiseau, Nicolas Guillou, Hervé Montagner, Alexandra |
author_facet | Régnier, Marion Polizzi, Arnaud Smati, Sarra Lukowicz, Céline Fougerat, Anne Lippi, Yannick Fouché, Edwin Lasserre, Frédéric Naylies, Claire Bétoulières, Colette Barquissau, Valentin Mouisel, Etienne Bertrand-Michel, Justine Batut, Aurélie Saati, Talal Al Canlet, Cécile Tremblay-Franco, Marie Ellero-Simatos, Sandrine Langin, Dominique Postic, Catherine Wahli, Walter Loiseau, Nicolas Guillou, Hervé Montagner, Alexandra |
author_sort | Régnier, Marion |
collection | PubMed |
description | Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparα(-) deficient mice (Pparα(−/−)) and in mice lacking Pparα only in hepatocytes (Pparα(hep−/−)). We provide evidence that Pparα deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARα as being essential to the prevention of NAFLD and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis. |
format | Online Article Text |
id | pubmed-7162950 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-71629502020-04-23 Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity Régnier, Marion Polizzi, Arnaud Smati, Sarra Lukowicz, Céline Fougerat, Anne Lippi, Yannick Fouché, Edwin Lasserre, Frédéric Naylies, Claire Bétoulières, Colette Barquissau, Valentin Mouisel, Etienne Bertrand-Michel, Justine Batut, Aurélie Saati, Talal Al Canlet, Cécile Tremblay-Franco, Marie Ellero-Simatos, Sandrine Langin, Dominique Postic, Catherine Wahli, Walter Loiseau, Nicolas Guillou, Hervé Montagner, Alexandra Sci Rep Article Peroxisome proliferator activated receptor α (PPARα) acts as a fatty acid sensor to orchestrate the transcription of genes coding for rate-limiting enzymes required for lipid oxidation in hepatocytes. Mice only lacking Pparα in hepatocytes spontaneously develop steatosis without obesity in aging. Steatosis can develop into non alcoholic steatohepatitis (NASH), which may progress to irreversible damage, such as fibrosis and hepatocarcinoma. While NASH appears as a major public health concern worldwide, it remains an unmet medical need. In the current study, we investigated the role of hepatocyte PPARα in a preclinical model of steatosis. For this, we used High Fat Diet (HFD) feeding as a model of obesity in C57BL/6 J male Wild-Type mice (WT), in whole-body Pparα(-) deficient mice (Pparα(−/−)) and in mice lacking Pparα only in hepatocytes (Pparα(hep−/−)). We provide evidence that Pparα deletion in hepatocytes promotes NAFLD and liver inflammation in mice fed a HFD. This enhanced NAFLD susceptibility occurs without development of glucose intolerance. Moreover, our data reveal that non-hepatocytic PPARα activity predominantly contributes to the metabolic response to HFD. Taken together, our data support hepatocyte PPARα as being essential to the prevention of NAFLD and that extra-hepatocyte PPARα activity contributes to whole-body lipid homeostasis. Nature Publishing Group UK 2020-04-16 /pmc/articles/PMC7162950/ /pubmed/32300166 http://dx.doi.org/10.1038/s41598-020-63579-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Régnier, Marion Polizzi, Arnaud Smati, Sarra Lukowicz, Céline Fougerat, Anne Lippi, Yannick Fouché, Edwin Lasserre, Frédéric Naylies, Claire Bétoulières, Colette Barquissau, Valentin Mouisel, Etienne Bertrand-Michel, Justine Batut, Aurélie Saati, Talal Al Canlet, Cécile Tremblay-Franco, Marie Ellero-Simatos, Sandrine Langin, Dominique Postic, Catherine Wahli, Walter Loiseau, Nicolas Guillou, Hervé Montagner, Alexandra Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity |
title | Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity |
title_full | Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity |
title_fullStr | Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity |
title_full_unstemmed | Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity |
title_short | Hepatocyte-specific deletion of Pparα promotes NAFLD in the context of obesity |
title_sort | hepatocyte-specific deletion of pparα promotes nafld in the context of obesity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7162950/ https://www.ncbi.nlm.nih.gov/pubmed/32300166 http://dx.doi.org/10.1038/s41598-020-63579-3 |
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