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.

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 for apobec-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.

• Authors: Yan Yang, Nazzareno Ballatori, Harold C Smith
• Journal: Molecular pharmacology (Mol Pharmacol) Vol. 61 Issue 2 Pg. 269-76 (Feb 2002) ISSN: 0026-895X [Print] United States
• PMID: 11809850 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apolipoprotein B-100
• Apolipoproteins B
• Gene Products, tat
• Lipoproteins
• RNA, Messenger
• RNA-Binding Proteins
• Recombinant Fusion Proteins
• APOBEC-1 Deaminase
• APOBEC1 protein, human
• Apobec1 protein, rat
• Cytidine Deaminase

Topics

• APOBEC-1 Deaminase
• Animals
• Apolipoprotein B-100
• Apolipoproteins B (drug effects, metabolism)
• Cells, Cultured
• Cytidine Deaminase
• Gene Products, tat (genetics, pharmacology)
• Hepatocytes (drug effects, physiology)
• Lipoproteins (metabolism)
• Male
• RNA Editing (drug effects)
• RNA, Messenger (drug effects, metabolism)
• RNA-Binding Proteins (genetics, pharmacology)
• Rats
• Rats, Sprague-Dawley
• Recombinant Fusion Proteins (pharmacology)
• Risk Factors