Research ArticleMetabolism

Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans

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Science Translational Medicine  27 Jan 2016:
Vol. 8, Issue 323, pp. 323ra12
DOI: 10.1126/scitranslmed.aad2195

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Making sense of antisense

Mipomersen is an FDA-approved antisense oligonucleotide that lowers low density lipoprotein (LDL) in patients with high cholesterol by targeting apolipoprotein B (apoB) synthesis. Although safe, how mipomersen works exactly in humans is unclear. Reyes-Soffer and colleagues found in healthy volunteers that the drug reduced levels of LDL and its precursor, very low density lipoproteins (VLDL), by increasing clearance of both of these vessel-clogging lipoproteins rather than reducing their secretion from the liver. The direct clearance of VLDL led to reduced production of LDL. Studies in mice and cell lines demonstrated how the liver compensates for reduced apoB synthesis to potentially avoid hepatic steatosis.


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.

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