title: Adenovirus-mediated transfer of a gene encoding cholesterol 7 alpha-hydroxylase into hamsters increases hepatic enzyme activity and reduces plasma total and low density lipoprotein cholesterol.
abstract: Clinical interventions that accelerate conversion of cholesterol to bile acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations. The initial and rate-limiting step in the bile acid biosynthetic pathway is catalyzed by hepatic cholesterol 7 alpha-hydroxylase. To examine the effects of transient primary overexpression of this enzyme on sterol metabolism and lipoprotein transport, we constructed a recombinant adenovirus in which a cDNA encoding rat 7 alpha-hydroxylase is expressed from the human cytomegalovirus immediate-early promoter (AdCMV7 alpha). Syrian hamsters administered AdCMV7 alpha intravenously accumulated transgene-specific mRNA in the liver and demonstrated a dose-dependent increase in hepatic microsomal 7 alpha-hydroxylase activity. The increased conversion of cholesterol to bile acids resulted in a compensatory increase in hepatic cholesterol synthesis. In addition, overexpression of 7 alpha-hydroxylase reduced the rate of LDL cholesterol entry into the plasma space and, in animals maintained on a Western-type diet, restored hepatic LDL receptor expression. As a consequence, plasma LDL concentrations fell by approximately 60% in animals maintained on control diet and by approximately 75% in animals consuming a Western-type diet. Plasma high density lipoprotein cholesterol levels were reduced to a lesser degree. These results demonstrate that transient upregulation of bile acid synthesis by direct transfer of a 7 alpha-hydroxylase gene favorably alters circulating lipoprotein profiles and suggest one potential molecular target for genetic strategies aimed at reducing cardiovascular risk.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235, USA.
authors.forename: D K
authors.initials: DK
authors.lastname: Spady
authors.forename: J A
authors.initials: JA
authors.lastname: Cuthbert
authors.forename: M N
authors.initials: MN
authors.lastname: Willard
authors.forename: R S
authors.initials: RS
authors.lastname: Meidell
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000097:blood*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood*; D002792:Cholestyramine Resin / Q000378:metabolism; D006224:Cricetinae; D018076:DNA, Complementary / Q000235:genetics; D004036:Diet, Atherogenic; D004790:Enzyme Induction; D005822:Genetic Vectors; D008297:Male; D008647:Mesocricetus; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014162:Transfection
chemical_list: D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D018076:DNA, Complementary; D011993:Recombinant Fusion Proteins; D002792:Cholestyramine Resin; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase