Hepatic expression of
apolipoprotein (
apo) B mRNA-editing
enzyme catalytic
polypeptide 1 (APOBEC-1) has been proposed as a gene
therapy approach for lowering plasma
low density lipoprotein (
LDL) levels. However, high-level expression of
APOBEC-1 in transgenic mouse and rabbit livers causes liver dysplasia and
hepatocellular carcinoma. To determine the physiological and pathological effects of low-level hepatic expression of
APOBEC-1, we used a 52-kb rat
APOBEC-1 genomic clone (RE4) to generate transgenic mice expressing low levels of
APOBEC-1 (2 to 5 times those in nontransgenic mice). Liver function, liver histology, editing of
apoB mRNA at the normal editing site (C6666), and abnormal editing at multiple sites (hyperediting) in these mice were compared with those in transgenic mice expressing intermediate (I-20) or high (I-28) levels of
APOBEC-1 in the liver. Hyperediting of
mRNA coding for the novel
APOBEC-1 target 1 (NAT1) was also examined. In the high-expressing I-28 line, 50% of the mice had palpable
tumors at 15 weeks of age, whereas in the intermediate-expressing I-20 line, 50% of the mice had evidence of liver
tumors after 1 year. In contrast, low-expressing RE4 mice had normal liver function and histology and did not develop liver
tumors when examined at 3 to 17 months of age. Moreover, hyperediting of
apoB and NAT1
mRNA in the liver was robust in the I-20 mice but barely detectable in the RE4 mice. The low-level expression resulted in sufficient
APOBEC-1 to edit essentially all
apoB mRNA at the normal editing site, virtually eliminating
apoB-100 and
LDL in the plasma of RE4 mice. When RE4 mice were crossed with human
apoB transgenic mice, which possess high plasma
LDL concentrations, plasma
LDL levels in the offspring were reduced to very low levels. These results indicates that long-term hepatic expression of
APOBEC-1 at low levels sufficient to eliminate
LDL does not cause apparent liver damage or liver
tumors in transgenic mice. RE4
APOBEC-1 transgenic mice should prove valuable for studying the roles of
apoB-containing
lipoproteins in lipid metabolism and
atherosclerosis.