Vol. 61, Issue 2, 269-276, February 2002

ACCELERATED 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

Departments of Biochemistry and Biophysics (H.C.S.) and Pathology and Laboratory Medicine (Y.Y., H.C.S.), and the Environmental Health Science (N.B., H.C.S.) and Cancer Centers (H.C.S.), University of Rochester School of Medicine and Dentistry, Rochester, New York

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.