title: Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Edward A. Doisy Department of Biochemistry and Molecular Biology (R.M.A., T.J.M., J.J.J, A.B.) and Center for Cardiovascular Research (R.M.A., T.J.M., A.B.), St. Louis University, St. Louis, MO.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Allen
authors.affiliation: From the Edward A. Doisy Department of Biochemistry and Molecular Biology (R.M.A., T.J.M., J.J.J, A.B.) and Center for Cardiovascular Research (R.M.A., T.J.M., A.B.), St. Louis University, St. Louis, MO.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Marquart
authors.affiliation: From the Edward A. Doisy Department of Biochemistry and Molecular Biology (R.M.A., T.J.M., J.J.J, A.B.) and Center for Cardiovascular Research (R.M.A., T.J.M., A.B.), St. Louis University, St. Louis, MO.
authors.forename: Jordan J
authors.initials: JJ
authors.lastname: Jesse
authors.affiliation: From the Edward A. Doisy Department of Biochemistry and Molecular Biology (R.M.A., T.J.M., J.J.J, A.B.) and Center for Cardiovascular Research (R.M.A., T.J.M., A.B.), St. Louis University, St. Louis, MO. abaldan1@slu.edu.
authors.forename: Angel
authors.initials: A
authors.lastname: Baldán
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000378:metabolism / Q000502:physiology; D002352:Carrier Proteins / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000502:physiology*; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000502:physiology*; D011973:Receptors, LDL / Q000502:physiology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000502:physiology; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D002352:Carrier Proteins; D008079:Lipoproteins, VLDL; D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D011973:Receptors, LDL; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C030106:very low density lipoprotein triglyceride; D052066:N-Ethylmaleimide-Sensitive Proteins
keywords: N-ethylmaleimide-sensitive factor; lipoproteins, VLDL; liver; miR-33; triglycerides
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