Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans
Gissette Reyes-Soffer, Byoung Moon, Antonio Hernandez-Ono, Marija Dionizovik-Dimanovski, Jhonsua Jimenez, Joseph Obunike, Tiffany Thomas, Colleen Ngai, Nelson Fontanez, Daniel S Donovan, Wahida Karmally, Stephen Holleran, Rajasekhar Ramakrishnan, Robert S Mittleman, Henry N Ginsberg, Gissette Reyes-Soffer, Byoung Moon, Antonio Hernandez-Ono, Marija Dionizovik-Dimanovski, Jhonsua Jimenez, Joseph Obunike, Tiffany Thomas, Colleen Ngai, Nelson Fontanez, Daniel S Donovan, Wahida Karmally, Stephen Holleran, Rajasekhar Ramakrishnan, Robert S Mittleman, Henry N Ginsberg
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.
Conflict of interest statement
Competing interests: R.S.M. was an employee of Sanofi-Genzyme during the active study phase. G.R.-S. reports grants and nonfinancial support from Merck during the conduct of the study. D.S.D. reports grants from Merck during the conduct of the study. H.N.G. reports grants from Merck during the conduct of the study and personal consulting fees from Merck outside the submitted work. H.N.G. was also on the Sanofi advisory board during the time that this work was done. All other authors declare that they have no competing interests.
Copyright © 2016, American Association for the Advancement of Science.
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Source: PubMed