Regulatable liver expression of the rabbit apolipoprotein B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1) in mice lacking endogenous APOBEC-1 leads to aberrant hyperediting
- HERSBERGER, Martin Institute of Clinical Chemistry, University Hospital Zurich, Raemistr. 100, CH-8091 Zurich, Switzerland,
- PATARROYO-WHITE, Susannah Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, 2550 23rd Street, Building 40, Third Floor, Cardiovascular Research Institute, University of California, San Francisco, CA 94141-9100, U.S.A.
- QIAN, Xiaobing Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, 2550 23rd Street, Building 40, Third Floor, Cardiovascular Research Institute, University of California, San Francisco, CA 94141-9100, U.S.A.
- ARNOLD, Kay S. Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, 2550 23rd Street, Building 40, Third Floor, Cardiovascular Research Institute, University of California, San Francisco, CA 94141-9100, U.S.A.
- ROHRER, Lucia Institute of Clinical Chemistry, University Hospital Zurich, Raemistr. 100, CH-8091 Zurich, Switzerland,
- BALESTRA, Maureen E. Gladstone Institute of Cardiovascular Disease, P.O. Box 419100, 2550 23rd Street, Building 40, Third Floor, Cardiovascular Research Institute, University of California, San Francisco, CA 94141-9100, U.S.A.
- INNERARITY, Thomas L. Department of Pathology, University of California, San Francisco, CA 94141-9100, U.S.A.
Published in:
- Biochemical Journal. - Portland Press Ltd.. - 2003, vol. 369, no. 2, p. 255-262
English
Apolipoprotein (apo) B mRNA editing is the deamination of C6666 to uridine, which results in translation of the apoB-48 protein instead of the genomically encoded apoB-100. ApoB-48-containing lipoproteins are cleared more rapidly from plasma and are less atherogenic than apoB-100-containing low-density lipoproteins (LDLs). In humans, the intestine predominantly produces apoB-48 whereas the liver secretes apoB-100 only. To evaluate a potential therapeutic use for liver-induced apoB mRNA editing in humans, we investigated the efficiency and safety of transgenic expression of apoB mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1) in the absence of endogenous editing in the mouse model. Here we show that regulatable tetO-mediated APOBEC-1 expression in the livers of gene-targeted mice lacking endogenous APOBEC-1 results in 30% apoB mRNA editing. In a time-course experiment, the expression of tetO-APOBEC-1 mRNA was suppressed within 2 days after mice were fed doxycycline and apoB mRNA editing and apoB-48 formation were suppressed within 4 days. However, tetO-APOBEC-1 expression resulted in regulatable aberrant hyperediting of several cytidines downstream of C6666 in apoB mRNA and in novel APOBEC-1 target 1 (NAT1) mRNA. Several of the cytidines in apoB mRNA were hyperedited to a level similar to that of C6666, although editing at C6666 was lower than that in wild-type mice. These results demonstrate that even moderate APOBEC-1 expression can lead to hyperediting, limiting the single-gene approach for gene therapy with APOBEC-1.
- Language
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- English
- Open access status
- green
- Identifiers
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- DOI 10.1042/bj20020694
- ISSN 0264-6021
- Persistent URL
- https://sonar.ch/global/documents/160267
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