Expression of human cholesterol 7alpha-hydroxylase in atherosclerosis-susceptible mice via adenovirus infection.
Adenovirus is a vector for the delivery of genes mainly to the liver. Short-term (approximately 3 days) studies using adenovirus transfection have provided valuable insights into how genes can complement normal and pathological phenotypes. When atherosclerosis-susceptible C57BL/6 mice were infected with an adenovirus vector containing the human 7alpha-hydroxylate cDNA (AV17h1) and fed on a chow diet, human 7alpha-hydroxylase mRNA and enzyme activity doubled compared with that in mice infected with an adenovirus vector (AV1Null) alone. In AV17h1-infected mice fed on a high fat cholic acid (HFCA) diet, mRNA expression and activity of both the endogenous and adenovirus (human) 7alpha-hydroxylase were repressed. AV17h1-infected mice fed on a HFCA diet and killed at mid-light had increased 7alpha-hydroxylase activity and mRNA compared with mice killed at mid-dark. Since expression of AV17h1 is driven by a constitutive Rous sarcoma virus promoter, the repression of human 7alpha-hydroxylase by the HFCA diet was unexpected. In spite of this post-transcriptional repression by the HFCA diet, AV17h1-infected mice expressed the human 7alpha-hydroxylase mRNA, causing its enzyme activity to be 3-fold greater than in AV1Null-infected mice. In AV17h1-infected mice, the 7alpha-hydroxylase enzyme activity varied as a linear function of human mRNA abundance. In conclusion, the accumulation of apolipoprotein B-containing lipoproteins in plasma of C57BL/6 mice fed on the HFCA diet was not reduced by longer-term (2 weeks) 7alpha-hydroxylase expression, probably because of its diminished expression caused by the diet and hepatic inflammation from the adenovirus infection. These results may suggest that adenovirus is effective in promoting longer-term (2 weeks) expression of 7alpha-hydroxylase.
Moore
G L
GL
Department of Biology, San Diego University, San Diego, CA 92182-0057, USA.
Drevon
C A
CA
Machleder
D
D
Trawick
J D
JD
McClelland
A
A
Roy
S
S
Lyons
R
R
Jambou
R
R
Davis
R A
RA
D000257:Adenoviridae Infections / Q000235:genetics*; D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology* / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics
D004041:Dietary Fats; D012333:RNA, Messenger; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase