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.
Apolipoprotein (apo) B mRNA editing is the deamination of C(6666) 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 C(6666) 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 C(6666), although editing at C(6666) 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.
Hersberger
Martin
M
Gladstone Institute of Cardiovascular Disease, University of California, Building 40, Third Floor, P.O. Box 419100, 2550 23rd Street, San Francisco, CA 94141-9100, U.S.A. hmr@kc.unizh.ch
Patarroyo-White
Susannah
S
Qian
Xiaobing
X
Arnold
Kay S
KS
Rohrer
Lucia
L
Balestra
Maureen E
ME
Innerarity
Thomas L
TL
D000071479:APOBEC-1 Deaminase; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008099:Liver / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D017393:RNA Editing; D011817:Rabbits; D019076:Transgenes; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D014280:Triglycerides; D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; D003564:Cytidine Deaminase