title: Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice.
abstract: 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.
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine Yale University School of Medicine, New Haven, CT, USA Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Leigh
authors.initials: L
authors.lastname: Goedeke
authors.affiliation: Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Salerno
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine Yale University School of Medicine, New Haven, CT, USA Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Ramírez
authors.affiliation: Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Center for Cardiovascular Research, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Allen
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, UK.
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Yin
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, UK.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Langley
authors.affiliation: Regulus Therapeutics, San Diego, CA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Esau
authors.affiliation: Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Amarylis
authors.initials: A
authors.lastname: Wanschel
authors.affiliation: Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine Yale University School of Medicine, New Haven, CT, USA Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA.
authors.forename: Yajaira
authors.initials: Y
authors.lastname: Suárez
authors.affiliation: Edward A. Doisy Department of Biochemistry and Molecular Biology, Center for Cardiovascular Research, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Angel
authors.initials: A
authors.lastname: Baldán
authors.affiliation: King's British Heart Foundation Centre, King's College London, London, UK.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.affiliation: Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA Integrative Cell Signaling and Neurobiology of Metabolism Program, Section of Comparative Medicine Yale University School of Medicine, New Haven, CT, USA Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, NY, USA Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA carlos.fernandez@yale.edu.
authors.forename: Carlos
authors.initials: C
authors.lastname: Fernández-Hernando
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005234:Fatty Liver; D020868:Gene Silencing; D050356:Lipid Metabolism / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood
chemical_list: D035683:MicroRNAs; C550417:Mirn33 microRNA, mouse; D016376:Oligonucleotides, Antisense; D014280:Triglycerides
keywords: cholesterol; fatty acids; hepatic steatosis; microRNA