Hepatic expression of the catalytic subunit of the apolipoprotein B mRNA editing enzyme (apobec-1) ameliorates hypercholesterolemia in LDL receptor-deficient rabbits.
Apolipoprotein (apo) B48, a protein contained in intestinally derived lipoprotein particles, is synthesized by post-transcriptional editing of apoB100 mRNA. This reaction is mediated by an enzyme complex that includes the catalytic subunit, apobec-1. The liver of most mammals, by contrast, contains only unedited apoB mRNA and secretes apoB100, the major protein component of plasma low-density lipoprotein (LDL). Because rabbits, like humans, fail to edit hepatic apoB100 mRNA, we introduced a recombinant adenovirus encoding apobec-1 into the livers of LDL receptor-defective rabbits to determine the impact on lipoprotein metabolism of hepatic apoB48 secretion. Transgene expression was mainly confined to the liver and was sustained for up to 3 weeks following virus administration, as evidenced by the presence of apobec-1 mRNA and the ability of hepatic S100 extracts to edit a synthetic apoB RNA template in vitro. The transient induction of hepatic apoB mRNA editing accompanied alterations in very-low-density lipoprotein (VLDL) size, the presence of apoB48 in fractions spanning the VLDL and LDL range, and modest reductions in total plasma cholesterol levels.
Kozarsky
K F
KF
Institute for Human Gene Therapy, University of Pennsylvania, Philadelphia 19104, USA.
Bonen
D K
DK
Giannoni
F
F
Funahashi
T
T
Wilson
J M
JM
Davidson
N O
NO
D000071479:APOBEC-1 Deaminase; D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D002384:Catalysis; D002784:Cholesterol / Q000097:blood; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D015316:Genetic Therapy; D006937:Hypercholesterolemia / Q000097:blood / Q000628:therapy*; D008099:Liver / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D011817:Rabbits; D011973:Receptors, LDL / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D001055:Apolipoproteins B; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D000071479:APOBEC-1 Deaminase; C000605089:APOBEC1 protein, human; D003564:Cytidine Deaminase