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

Allen RM, Marquart TJ, Jesse JJ, Baldán A
Circ Res. 2014 115 (1): 10-22

PMID: 24753547 · PMCID: PMC4108429 · DOI:10.1161/CIRCRESAHA.115.303100

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.

© 2014 American Heart Association, Inc.

MeSH Terms (14)

Animals Apolipoprotein B-100 Apolipoproteins B Carrier Proteins Hepatocytes Lipoproteins, VLDL Male Mice Mice, Inbred C57BL MicroRNAs N-Ethylmaleimide-Sensitive Proteins Receptors, LDL Sterol Regulatory Element Binding Protein 2 Triglycerides

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