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Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice
Open accessAbstract
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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“Additionally, some studies of long-term anti-miR-33 treatment have reported deleterious effects including increased circulating levels of triglycerides (TAGs) and the development of hepatic steatosis (Allen et al., 2014; Goedeke et al., 2014).”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Goedeke et al., 2014
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“the hypertriglyceridemia and hepatic steatosis observed in some long term anti-miR-33 studies (Allen et al., 2014; Goedeke et al., 2014)”
From Genetic dissection of the impact of miR-33a and miR-33b during the progression of atherosclerosis (2017) · cites this paper as Goedeke et al., 2014
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Metadata
- Authors
- Goedeke, L., Salerno, A., Ramírez, C. M., Guo, L., Allen, R. M., Yin, X., Langley, S. R., Esau, C., Wanschel, A., Fisher, E. A., Suárez, Y., Baldán, A., Mayr, M., & Fernández‐Hernando, C.
- Affiliations
- Yale University (US)
- New York University (US)
- Saint Louis University (US)
- King's College London (GB)
- Regulus Therapeutics (United States) (US)
- ORCID
- Venue
- EMBO Molecular Medicine
- Published
- 2014-07-18
- Volume
- 6
- Issue
- 9
- Pages
- 1133-1141
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC4197861
- OpenAlex
- W2142082511
- Cited by
- 145
- References
- 32
- Citations by year
- 2026: 2 · 2025: 12 · 2024: 6 · 2023: 8 · 2022: 10 · 2021: 10 · 2020: 11 · 2019: 12 · 2018: 11 · 2017: 17 · 2016: 23 · 2015: 21 · 2014: 2
- FWCI
- 20.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Funders
- National Institutes of Health (R01HL107953, R01HL107953‐04S1, R01HL106063, 1F31AG043318, R01HL107794)
- Foundation Leducq Transatlantic Network of Excellence in Cardiovascular Research
- Heart Research UK
- Department of Health via the National Institute for Health Research
- Biomedical Research Centre
- NHS Foundation Trust
- King's College London
- King's College Hospital NHS Foundation Trust
- British Heart Foundation
- AHA Predoctoral Fellowship (11PRE7240026)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Keywords
- miR-33, antisense oligonucleotides, hypertriglyceridemia, hepatic steatosis, fatty acid synthesis, acetyl-CoA carboxylase, fatty acid synthase, SREBP, high-fat diet, HDL cholesterol, reverse cholesterol transport, atherosclerosis
- MeSH terms
- Animals, Fatty Liver, Liver, Male, Mice, Inbred C57BL, Triglycerides, Oligonucleotides, Antisense, Gene Silencing, MicroRNAs, Lipid Metabolism, Diet, High-Fat
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