| First Author | Allen RM | Year | 2014 |
| Journal | Circ Res | Volume | 115 |
| Issue | 1 | Pages | 10-22 |
| PubMed ID | 24753547 | Mgi Jnum | J:247013 |
| Mgi Id | MGI:5921509 | Doi | 10.1161/CIRCRESAHA.115.303100 |
| Citation | Allen RM, et al. (2014) Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33. Circ Res 115(1):10-22 |
| abstractText | 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. |
