title: Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans.
abstract: Mipomersen is a 20mer antisense oligonucleotide (ASO) that inhibits apolipoprotein B (apoB) synthesis; its low-density lipoprotein (LDL)-lowering effects should therefore result from reduced secretion of very-low-density lipoprotein (VLDL). We enrolled 17 healthy volunteers who received placebo injections weekly for 3 weeks followed by mipomersen weekly for 7 to 9 weeks. Stable isotopes were used after each treatment to determine fractional catabolic rates and production rates of apoB in VLDL, IDL (intermediate-density lipoprotein), and LDL, and of triglycerides in VLDL. Mipomersen significantly reduced apoB in VLDL, IDL, and LDL, which was associated with increases in fractional catabolic rates of VLDL and LDL apoB and reductions in production rates of IDL and LDL apoB. Unexpectedly, the production rates of VLDL apoB and VLDL triglycerides were unaffected. Small interfering RNA-mediated knockdown of apoB expression in human liver cells demonstrated preservation of apoB secretion across a range of apoB synthesis. Titrated ASO knockdown of apoB mRNA in chow-fed mice preserved both apoB and triglyceride secretion. In contrast, titrated ASO knockdown of apoB mRNA in high-fat-fed mice resulted in stepwise reductions in both apoB and triglyceride secretion. Mipomersen lowered all apoB lipoproteins without reducing the production rate of either VLDL apoB or triglyceride. Our human data are consistent with long-standing models of posttranscriptional and posttranslational regulation of apoB secretion and are supported by in vitro and in vivo experiments. Targeting apoB synthesis may lower levels of apoB lipoproteins without necessarily reducing VLDL secretion, thereby lowering the risk of steatosis associated with this therapeutic strategy.
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. gr2104@cumc.columbia.edu hng1@cumc.columbia.edu.
authors.forename: Gissette
authors.initials: G
authors.lastname: Reyes-Soffer
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Byoung
authors.initials: B
authors.lastname: Moon
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez-Ono
authors.forename: Marija
authors.initials: M
authors.lastname: Dionizovik-Dimanovski
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Marija
authors.initials: M
authors.lastname: Dionizovick-Dimanovski
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Jhonsua
authors.initials: J
authors.lastname: Jimenez
authors.affiliation: Biological Sciences Department, New York City College of Technology, 300 Jay Street, Brooklyn, NY 11201, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Obunike
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Tiffany
authors.initials: T
authors.lastname: Thomas
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Colleen
authors.initials: C
authors.lastname: Ngai
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Nelson
authors.initials: N
authors.lastname: Fontanez
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Donovan
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Wahida
authors.initials: W
authors.lastname: Karmally
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Holleran
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Ramakrishnan
authors.affiliation: Sanofi-Genzyme, 500 Kendall Street, Cambridge, MA 02142, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittleman
authors.affiliation: Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA. gr2104@cumc.columbia.edu hng1@cumc.columbia.edu.
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D053299:Apolipoprotein B-100 / Q000037:antagonists & inhibitors*; D001055:Apolipoproteins B / Q000235:genetics; D005260:Female; D064368:Healthy Volunteers; D056945:Hep G2 Cells; D006801:Humans; D053419:Lipoproteins, IDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009841:Oligonucleotides / Q000737:chemistry; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D055815:Young Adult
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D034741:RNA, Small Interfering; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; C524142:mipomersen
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