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Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice
Plasma high-density lipoprotein (HDL) levels show a strong inverse correlation with atherosclerotic vascular disease. Previous studies have demonstrated that antagonism of miR-33 in vivo increases circulating HDL and reverse cholesterol transport (RCT), thereby reducing the progression and enhancing...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Blackwell Publishing Ltd
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197861/ https://www.ncbi.nlm.nih.gov/pubmed/25038053 http://dx.doi.org/10.15252/emmm.201404046 |
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author | Goedeke, Leigh Salerno, Alessandro Ramírez, Cristina M Guo, Liang Allen, Ryan M Yin, Xiaoke Langley, Sarah R Esau, Christine Wanschel, Amarylis Fisher, Edward A Suárez, Yajaira Baldán, Angel Mayr, Manuel Fernández-Hernando, Carlos |
author_facet | Goedeke, Leigh Salerno, Alessandro Ramírez, Cristina M Guo, Liang Allen, Ryan M Yin, Xiaoke Langley, Sarah R Esau, Christine Wanschel, Amarylis Fisher, Edward A Suárez, Yajaira Baldán, Angel Mayr, Manuel Fernández-Hernando, Carlos |
author_sort | Goedeke, Leigh |
collection | PubMed |
description | Plasma high-density lipoprotein (HDL) levels show a strong inverse correlation with atherosclerotic vascular disease. Previous studies have demonstrated that antagonism of miR-33 in vivo increases circulating HDL and reverse cholesterol transport (RCT), thereby reducing the progression and enhancing the regression of atherosclerosis. While the efficacy of short-term anti-miR-33 treatment has been previously studied, the long-term effect of miR-33 antagonism in vivo remains to be elucidated. Here, we show that long-term therapeutic silencing of miR-33 increases circulating triglyceride (TG) levels and lipid accumulation in the liver. These adverse effects were only found when mice were fed a high-fat diet (HFD). Mechanistically, we demonstrate that chronic inhibition of miR-33 increases the expression of genes involved in fatty acid synthesis such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the livers of mice treated with miR-33 antisense oligonucleotides. We also report that anti-miR-33 therapy enhances the expression of nuclear transcription Y subunit gamma (NFYC), a transcriptional regulator required for DNA binding and full transcriptional activation of SREBP-responsive genes, including ACC and FAS. Taken together, these results suggest that persistent inhibition of miR-33 when mice are fed a high-fat diet (HFD) might cause deleterious effects such as moderate hepatic steatosis and hypertriglyceridemia. These unexpected findings highlight the importance of assessing the effect of chronic inhibition of miR-33 in non-human primates before we can translate this therapy to humans. |
format | Online Article Text |
id | pubmed-4197861 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Blackwell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-41978612014-11-03 Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice Goedeke, Leigh Salerno, Alessandro Ramírez, Cristina M Guo, Liang Allen, Ryan M Yin, Xiaoke Langley, Sarah R Esau, Christine Wanschel, Amarylis Fisher, Edward A Suárez, Yajaira Baldán, Angel Mayr, Manuel Fernández-Hernando, Carlos EMBO Mol Med Reports Plasma high-density lipoprotein (HDL) levels show a strong inverse correlation with atherosclerotic vascular disease. Previous studies have demonstrated that antagonism of miR-33 in vivo increases circulating HDL and reverse cholesterol transport (RCT), thereby reducing the progression and enhancing the regression of atherosclerosis. While the efficacy of short-term anti-miR-33 treatment has been previously studied, the long-term effect of miR-33 antagonism in vivo remains to be elucidated. Here, we show that long-term therapeutic silencing of miR-33 increases circulating triglyceride (TG) levels and lipid accumulation in the liver. These adverse effects were only found when mice were fed a high-fat diet (HFD). Mechanistically, we demonstrate that chronic inhibition of miR-33 increases the expression of genes involved in fatty acid synthesis such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in the livers of mice treated with miR-33 antisense oligonucleotides. We also report that anti-miR-33 therapy enhances the expression of nuclear transcription Y subunit gamma (NFYC), a transcriptional regulator required for DNA binding and full transcriptional activation of SREBP-responsive genes, including ACC and FAS. Taken together, these results suggest that persistent inhibition of miR-33 when mice are fed a high-fat diet (HFD) might cause deleterious effects such as moderate hepatic steatosis and hypertriglyceridemia. These unexpected findings highlight the importance of assessing the effect of chronic inhibition of miR-33 in non-human primates before we can translate this therapy to humans. Blackwell Publishing Ltd 2014-09 2014-07-18 /pmc/articles/PMC4197861/ /pubmed/25038053 http://dx.doi.org/10.15252/emmm.201404046 Text en © 2014 The Authors. Published under the terms of the CC BY 4.0 license http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Reports Goedeke, Leigh Salerno, Alessandro Ramírez, Cristina M Guo, Liang Allen, Ryan M Yin, Xiaoke Langley, Sarah R Esau, Christine Wanschel, Amarylis Fisher, Edward A Suárez, Yajaira Baldán, Angel Mayr, Manuel Fernández-Hernando, Carlos Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice |
title | Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice |
title_full | Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice |
title_fullStr | Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice |
title_full_unstemmed | Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice |
title_short | Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice |
title_sort | long-term therapeutic silencing of mir-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice |
topic | Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4197861/ https://www.ncbi.nlm.nih.gov/pubmed/25038053 http://dx.doi.org/10.15252/emmm.201404046 |
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