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Rapid CommunicationAccelerated Communication

Apolipoprotein B mRNA Editing and the Reduction in Synthesis and Secretion of the Atherogenic Risk Factor, Apolipoprotein B100 Can Be Effectively Targeted through TAT-Mediated Protein Transduction

Yan Yang, Nazzareno Ballatori and Harold C. Smith
Molecular Pharmacology February 2002, 61 (2) 269-276; DOI: https://doi.org/10.1124/mol.61.2.269
Yan Yang
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Nazzareno Ballatori
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Harold C. Smith
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Abstract

Hepatic very-low-density lipoprotein particles (VLDL) containing full-length apolipoprotein B100 are metabolized in the blood stream to low-density lipoprotein (LDL) particles, whose elevated levels increase the risk of atherosclerosis. Statins and bile-acid sequestrants are effective LDL-lowering therapies for many patients. Development of alternative therapies remains important for patients with adverse reactions to conventional therapy, with defects in the LDL receptor-dependent lipoprotein uptake pathway and for intervention in children. Editing of apoB mRNA by the enzyme APOBEC-1 changes a glutamine codon to a stop codon, leading to the synthesis and secretion of apoB48-containing VLDL, which are rapidly cleared before they can be metabolized to LDL. Human liver does not edit apoB mRNA because it does not express APOBEC-1. Although initially promising, enthusiasm forapobec-1 gene therapy for hypercholesterolemia was blunted by the finding that uncontrolled transgenic expression of APOBEC-1 led to nonspecific editing of mRNAs and pathology. We demonstrate that APOBEC-1 fused to TAT entered primary hepatocytes, where it induced a transient increase in mRNA editing activity and enhanced synthesis and secretion of VLDL containing apoB48. Protein transduction of APOBEC-1 transiently stimulated high levels of apoB mRNA editing in a dose-dependent manner without loss of fidelity. These results suggested that apoB mRNA editing should be re-evaluated as a LDL-lowering therapeutic target in the new context of protein transduction therapy.

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Molecular Pharmacology: 61 (2)
Molecular Pharmacology
Vol. 61, Issue 2
1 Feb 2002
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Rapid CommunicationAccelerated Communication

Apolipoprotein B mRNA Editing and the Reduction in Synthesis and Secretion of the Atherogenic Risk Factor, Apolipoprotein B100 Can Be Effectively Targeted through TAT-Mediated Protein Transduction

Yan Yang, Nazzareno Ballatori and Harold C. Smith
Molecular Pharmacology February 1, 2002, 61 (2) 269-276; DOI: https://doi.org/10.1124/mol.61.2.269

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Rapid CommunicationAccelerated Communication

Apolipoprotein B mRNA Editing and the Reduction in Synthesis and Secretion of the Atherogenic Risk Factor, Apolipoprotein B100 Can Be Effectively Targeted through TAT-Mediated Protein Transduction

Yan Yang, Nazzareno Ballatori and Harold C. Smith
Molecular Pharmacology February 1, 2002, 61 (2) 269-276; DOI: https://doi.org/10.1124/mol.61.2.269
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