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Cited by 38Cholesterol and Lipid MetabolismMicroRNA in disease regulationLipid metabolism and disorders

Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33

Open access
Allen, Ryan M., Marquart, Tyler J., Jesse, Jordan J., Baldán, Ángel·2014·Circulation Research
DOI 10.1161/circresaha.115.303100PMC PMC4108429
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Abstract

Rationale : Several reports suggest that antisense oligonucleotides against miR-33 might reduce cardiovascular risk in patients by accelerating the reverse cholesterol transport pathway. However, conflicting reports exist about the impact of anti-miR-33 therapy on the levels of very low-density lipoprotein-triglycerides (VLDL-TAG). Objective : We test the hypothesis that miR-33 controls hepatic VLDL-TAG secretion. Methods and Results : Using therapeutic silencing of miR-33 and adenoviral overexpression of miR-33, we show that miR-33 limits hepatic secretion of VLDL-TAG by targeting N-ethylmaleimide-sensitive factor (NSF), both in vivo and in primary hepatocytes. We identify conserved sequences in the 3′UTR of NSF as miR-33 responsive elements and show that Nsf is specifically recruited to the RNA-induced silencing complex following induction of miR-33. In pulse-chase experiments, either miR-33 overexpression or knock-down of Nsf lead to decreased secretion of apolipoproteins and TAG in primary hepatocytes, compared with control cells. Importantly, Nsf rescues miR-33-dependent reduced secretion. Finally, we show that overexpression of Nsf in vivo increases global hepatic secretion and raises plasma VLDL-TAG. Conclusions : Together, our data reveal key roles for the miR-33–NSF axis during hepatic secretion and suggest that caution should be taken with anti-miR-33-based therapies because they might raise proatherogenic VLDL-TAG levels.

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  • Some studies of long-term anti-miR-33 treatment have reported deleterious effects including increased circulating levels of triglycerides and the development of hepatic steatosis.

    “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 Allen et al., 2014

    The Results section reports that 11 weeks of anti-miR-33 treatment raised circulating VLDL-TAG in mice. It also reports no increase in hepatic TAG. The Discussion mentions hepatic steatosis only in a different study of genetically miR-33-deficient mice fed a high-fat diet, not as an effect of long-term anti-miR-33 treatment. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Long-term anti-miR-33 studies observed hypertriglyceridemia and hepatic steatosis.

    “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 Allen et al., 2014

    The Results section reports sustained elevated plasma TAG after 11 weeks of anti-miR-33 treatment, supporting the hypertriglyceridemia portion. It reports no change in hepatic TAG in those mice, so this study does not support hepatic steatosis after anti-miR-33 treatment. The Discussion mentions steatosis in a separate study of miR-33 knockout mice fed a high-fat diet. Page numbers are not provided in our copy. (LLM, conf=0.91)

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Cited by

Sorted by citations

Authors
Allen, R. M., Marquart, T. J., Jesse, J. J., & Baldán, Á.
Affiliations
Saint Louis University (US)
ORCID
Venue
Circulation Research
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-06-20
Volume
115
Issue
1
Pages
10-22
ISSN
  • 0009-7330 (ISSN-L)
  • 1524-4571
DOI
10.1161/circresaha.115.303100
PMC
PMC4108429
OpenAlex
W2161983036
Cited by
38
References
10
Citations by year
2025: 2 · 2022: 1 · 2021: 3 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 9 · 2015: 8 · 2014: 2
FWCI
8.60
Type
journal article
Language
en
Open access
Locations
  • Circulation Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Heart Association
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (HL107794, R01HL107794)
Topics
  • Health Sciences › Medicine › Surgery › 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, N-ethylmaleimide-sensitive factor, NSF, very low density lipoprotein secretion, hepatic triglyceride secretion, antisense therapy, RNA-induced silencing complex, 3' UTR binding, apolipoprotein secretion, reverse cholesterol transport, atherosclerosis risk, hepatocytes
MeSH terms
Animals, Apolipoproteins B, Carrier Proteins, Lipoproteins, VLDL, Male, Mice, Inbred C57BL, Receptors, LDL, Triglycerides, Hepatocytes, MicroRNAs, Mice, Sterol Regulatory Element Binding Protein 2, N-Ethylmaleimide-Sensitive Proteins, Apolipoprotein B-100

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