Academic Commons

Articles

Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans

Soffer, Gissette; Moon, Byoung C.; Hernandez-Ono, Antonio; Dionizovik-Dimanovski, Marija; Jimenez, Jhonsua; Obunike, Joseph; Thomas, Tiffany; Karmally, Wahida; Ngai, Colleen I.; Donovan Jr, Daniel S.; Fontanez, Nelson; Ramakrishnan, Rajasekhar; Holleran, Stephen F.; Mittleman, Robert S.; Ginsberg, Henry N.

Mipomersen (Kynamro®) is an antisense oligonucleotide (ASO) that inhibits apolipoprotein B (apoB) synthesis; its LDL lowering effects should, therefore, result from reduced secretion of VLDL. We enrolled 17 healthy volunteers who received placebo injections weekly for 3-wks followed by mipomersen weekly for 7-9 wks. Stable isotopes were used after each treatment to determine fractional catabolic rates (FCRs) and production rates (PRs) of apoB in VLDL, IDL, and LDL, and of TG in VLDL. Mipomersen significantly reduced apoB in VLDL, IDL, and LDL associated with increases in FCRs of VLDL and LDL apoB and reductions in PRs of IDL and LDL apoB. Unexpectedly, the PRs of VLDL apoB and VLDL TG were unaffected. siRNA knockdown of apoB expression in HepG2 cells demonstrated preservation of apoB secretion across a range of apoB synthesis. Titrated ASO knockdown of apoB mRNA in chow-fed mice showed preservation of both apoB and TG secretion. In contrast, titrated ASO knockdown of apoB mRNA in high fat fed mice resulted in stepwise reductions of both apoB and TG secretion. Mipomersen lowered all apoB-lipoproteins without reducing the PR of either VLDL apoB or TG. Our first-in-human data are consistent with longstanding models of post-transcriptional and post-translational regulation of apoB secretion, and are supported by experiments with siRNA in HepG2 cells and ASO in mice. These results indicate that targeting apoB synthesis can lower levels of apoB-lipoproteins without necessarily reducing VLDL secretion, thereby reducing the risk of steatosis associated with this therapeutic strategy.

Files

  • thumnail for Final_Draft_of_Manuscript.pdf Final_Draft_of_Manuscript.pdf application/pdf 634 KB Download File

More Information

Published In
Science Translational Medicine
Publisher DOI
https://doi.org/10.1126/scitranslmed.aad2195
Volume
8
Issue
323
Pages
323 - 332
Academic Units
Medicine
Pathology and Cell Biology
Irving Institute for Clinical and Translational Research
Pediatrics
Academic Commons provides global access to research and scholarship produced at Columbia University, Barnard College, Teachers College, Union Theological Seminary and Jewish Theological Seminary. Academic Commons is managed by the Columbia University Libraries.