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Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver

MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of...

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Autores principales: Kurtz, C. Lisa, Fannin, Emily E., Toth, Cynthia L., Pearson, Daniel S., Vickers, Kasey C., Sethupathy, Praveen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526858/
https://www.ncbi.nlm.nih.gov/pubmed/26246194
http://dx.doi.org/10.1038/srep12911
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author Kurtz, C. Lisa
Fannin, Emily E.
Toth, Cynthia L.
Pearson, Daniel S.
Vickers, Kasey C.
Sethupathy, Praveen
author_facet Kurtz, C. Lisa
Fannin, Emily E.
Toth, Cynthia L.
Pearson, Daniel S.
Vickers, Kasey C.
Sethupathy, Praveen
author_sort Kurtz, C. Lisa
collection PubMed
description MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia.
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spelling pubmed-45268582015-08-07 Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver Kurtz, C. Lisa Fannin, Emily E. Toth, Cynthia L. Pearson, Daniel S. Vickers, Kasey C. Sethupathy, Praveen Sci Rep Article MicroRNAs (miRNAs) are important regulators and potential therapeutic targets of metabolic disease. In this study we show by in vivo administration of locked nucleic acid (LNA) inhibitors that suppression of endogenous miR-29 lowers plasma cholesterol levels by ~40%, commensurate with the effect of statins, and reduces fatty acid content in the liver by ~20%. Whole transcriptome sequencing of the liver reveals 883 genes dysregulated (612 down, 271 up) by inhibition of miR-29. The set of 612 down-regulated genes are most significantly over-represented in lipid synthesis pathways. Among the up-regulated genes are the anti-lipogenic deacetylase sirtuin 1 (Sirt1) and the anti-lipogenic transcription factor aryl hydrocarbon receptor (Ahr), the latter of which we demonstrate is a direct target of miR-29. In vitro radiolabeled acetate incorporation assays confirm that pharmacologic inhibition of miR-29 significantly reduces de novo cholesterol and fatty acid synthesis. Our findings indicate that miR-29 controls hepatic lipogenic programs, likely in part through regulation of Ahr and Sirt1, and therefore may represent a candidate therapeutic target for metabolic disorders such as dyslipidemia. Nature Publishing Group 2015-08-06 /pmc/articles/PMC4526858/ /pubmed/26246194 http://dx.doi.org/10.1038/srep12911 Text en Copyright © 2015, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Article
Kurtz, C. Lisa
Fannin, Emily E.
Toth, Cynthia L.
Pearson, Daniel S.
Vickers, Kasey C.
Sethupathy, Praveen
Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver
title Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver
title_full Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver
title_fullStr Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver
title_full_unstemmed Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver
title_short Inhibition of miR-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver
title_sort inhibition of mir-29 has a significant lipid-lowering benefit through suppression of lipogenic programs in liver
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4526858/
https://www.ncbi.nlm.nih.gov/pubmed/26246194
http://dx.doi.org/10.1038/srep12911
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