Gene transfer of cytidine deaminase apoBEC-1 lowers lipoprotein(a) in transgenic mice and induces apolipoprotein B editing in rabbits.
Apolipoprotein (apo) B100 is an essential component of low-density lipoproteins (LDL) and lipoprotein(a) [Lp(a)]. In mammals, apoB can be edited post-transcriptionally to encode a truncated form of apoB (apoB48) that is unable to form either of these atherogenic lipoproteins. To study the effect of increasing hepatic apoB editing activity on formation of Lp(a), a recombinant adenovirus encoding rat apoBEC-1, the cytidine deaminase component of the apoB mRNA editing complex, was administered to human apoB/apo(a) transgenic mice. This resulted in expression of apoBEC-1 in hepatocytes of these mice, increased hepatic editing of human apoB mRNA, and decreased plasma levels of human apoB100 and Lp(a). The apoBEC-1 recombinant adenovirus was also administered to rabbits, an animal which, like humans, naturally lacks hepatic apoB editing. Expression of the exogenous apoBEC-1 in rabbit liver resulted in editing of up to 10% of apoB mRNA. Hepatic apoB editing was associated with lower LDL levels in these rabbits relative to those treated with a control adenovirus. However, LDL levels were elevated significantly in both animals as a result of adenovirus injection. These studies demonstrate that introduction of the cytidine deaminase apoBEC-1 is sufficient to induce hepatic apoB editing in an animal lacking this activity, and that induction of editing could serve as a novel approach for lowering plasma concentrations of the atherogenic lipoproteins Lp(a) and LDL.
Hughes
S D
SD
Lawrence Berkeley Laboratory, University of California, Berkeley 94720, USA.
Rouy
D
D
Navaratnam
N
N
Scott
J
J
Rubin
E M
EM
D000071479:APOBEC-1 Deaminase; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics*; D001483:Base Sequence; D002457:Cell Extracts; D003564:Cytidine Deaminase / Q000235:genetics*; D003587:Cytomegalovirus / Q000235:genetics; D017931:DNA Primers; D005240:Feasibility Studies; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D017270:Lipoprotein(a) / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017393:RNA Editing / Q000235:genetics*; D012333:RNA, Messenger; D011817:Rabbits; D051381:Rats; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D001055:Apolipoproteins B; D002457:Cell Extracts; D017931:DNA Primers; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D012333:RNA, Messenger; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse; C000605091:Apobec1 protein, rat; D003564:Cytidine Deaminase