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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Blackwell Publishing Ltd 2014
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.
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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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