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Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice
The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) regulates the host response to short-term fasting by inducing hepatic transcriptional programming of ketogenesis, fatty acid oxidation and transport, and autophagy. This adaptation is ineffective in chronicall...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997242/ https://www.ncbi.nlm.nih.gov/pubmed/35419389 http://dx.doi.org/10.3389/fnut.2022.831879 |
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author | Suh, Ji Ho Kim, Kang Ho Conner, Margaret E. Moore, David D. Preidis, Geoffrey A. |
author_facet | Suh, Ji Ho Kim, Kang Ho Conner, Margaret E. Moore, David D. Preidis, Geoffrey A. |
author_sort | Suh, Ji Ho |
collection | PubMed |
description | The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) regulates the host response to short-term fasting by inducing hepatic transcriptional programming of ketogenesis, fatty acid oxidation and transport, and autophagy. This adaptation is ineffective in chronically undernourished individuals, among whom dyslipidemia and hepatic steatosis are common. We recently reported that hepatic PPARα protein is profoundly depleted in male mice undernourished by a low-protein, low-fat diet. Here, we identify PPARα as a deacetylation target of the NAD-dependent deacetylase sirtuin-1 (SIRT1) and link this to the decrease in PPARα protein levels in undernourished liver. Livers from undernourished male mice expressed high levels of SIRT1, with decreased PPARα acetylation and strongly decreased hepatic PPARα protein. In cultured hepatocytes, PPARα protein levels were decreased by transiently transfecting constitutively active SIRT1 or by treating cells with the potent SIRT1 activator resveratrol, while silencing SIRT1 increased PPARα protein levels. SIRT1 expression is correlated with increased PPARα ubiquitination, suggesting that protein loss is due to proteasomal degradation. In accord with these findings, the dramatic loss of hepatic PPARα in undernourished male mice was completely restored by treating mice with the proteasome inhibitor bortezomib. Similarly, treating undernourished mice with the SIRT1 inhibitor selisistat/EX-527 completely restored hepatic PPARα protein. These data suggest that induction of SIRT1 in undernutrition results in hepatic PPARα deacetylation, ubiquitination, and degradation, highlighting a new mechanism that mediates the liver's failed adaptive metabolic responses in chronic undernutrition. |
format | Online Article Text |
id | pubmed-8997242 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89972422022-04-12 Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice Suh, Ji Ho Kim, Kang Ho Conner, Margaret E. Moore, David D. Preidis, Geoffrey A. Front Nutr Nutrition The nutrient sensing nuclear receptor peroxisome proliferator-activated receptor-α (PPARα) regulates the host response to short-term fasting by inducing hepatic transcriptional programming of ketogenesis, fatty acid oxidation and transport, and autophagy. This adaptation is ineffective in chronically undernourished individuals, among whom dyslipidemia and hepatic steatosis are common. We recently reported that hepatic PPARα protein is profoundly depleted in male mice undernourished by a low-protein, low-fat diet. Here, we identify PPARα as a deacetylation target of the NAD-dependent deacetylase sirtuin-1 (SIRT1) and link this to the decrease in PPARα protein levels in undernourished liver. Livers from undernourished male mice expressed high levels of SIRT1, with decreased PPARα acetylation and strongly decreased hepatic PPARα protein. In cultured hepatocytes, PPARα protein levels were decreased by transiently transfecting constitutively active SIRT1 or by treating cells with the potent SIRT1 activator resveratrol, while silencing SIRT1 increased PPARα protein levels. SIRT1 expression is correlated with increased PPARα ubiquitination, suggesting that protein loss is due to proteasomal degradation. In accord with these findings, the dramatic loss of hepatic PPARα in undernourished male mice was completely restored by treating mice with the proteasome inhibitor bortezomib. Similarly, treating undernourished mice with the SIRT1 inhibitor selisistat/EX-527 completely restored hepatic PPARα protein. These data suggest that induction of SIRT1 in undernutrition results in hepatic PPARα deacetylation, ubiquitination, and degradation, highlighting a new mechanism that mediates the liver's failed adaptive metabolic responses in chronic undernutrition. Frontiers Media S.A. 2022-03-28 /pmc/articles/PMC8997242/ /pubmed/35419389 http://dx.doi.org/10.3389/fnut.2022.831879 Text en Copyright © 2022 Suh, Kim, Conner, Moore and Preidis. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Nutrition Suh, Ji Ho Kim, Kang Ho Conner, Margaret E. Moore, David D. Preidis, Geoffrey A. Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice |
title | Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice |
title_full | Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice |
title_fullStr | Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice |
title_full_unstemmed | Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice |
title_short | Hepatic PPARα Is Destabilized by SIRT1 Deacetylase in Undernourished Male Mice |
title_sort | hepatic pparα is destabilized by sirt1 deacetylase in undernourished male mice |
topic | Nutrition |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8997242/ https://www.ncbi.nlm.nih.gov/pubmed/35419389 http://dx.doi.org/10.3389/fnut.2022.831879 |
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