ADENOVIRUS-MEDIATED TRANSFER OF A GENE ENCODING CHOLESTEROL 7-ALPHA-HYDROXYLASE INTO HAMSTERS INCREASES HEPATIC ENZYME-ACTIVITY AND REDUCESPLASMA TOTAL AND LOW-DENSITY-LIPOPROTEIN CHOLESTEROL

Clinical interventions that accelerate conversion of cholesterol to bi le acids reduce circulating low density lipoprotein (LDL) cholesterol concentrations, The initial and rate-limiting step in the bile acid bi osynthetic pathway is catalyzed by hepatic cholesterol 7 alpha-hydroxy lase. To examine the effects of transient primary overexpression of th is enzyme on sterol metabolism and lipoprotein transport, we construct ed a recombinant adenovirus in which a cDNA encoding rat 7 alpha-hydro xylase is expressed from the human cytomegalovirus immediate-early pro moter (AdCMV7 alpha). Syrian hamsters administered AdCMV7 alpha intrav enously accumulated transgene-specific mRNA in the liver and demonstra ted a dose-dependent increase in hepatic microsomal 7 alpha-hydroxylas e activity, The increased conversion of cholesterol to bile acids resu lted in a compensatory increase in hepatic cholesterol synthesis, In a ddition, 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 c onsequence, plasma LDL concentrations fell by similar to 60% in animal s maintained on control diet and by similar to 75% in animals consumin g a Western-type diet, Plasma high density lipoprotein cholesterol lev els were reduced to a lesser degree. These results demonstrate that tr ansient upregulation of bile acid synthesis by direct transfer of a 7 alpha-hydroxylase gene favorably alters circulating lipoprotein profil es and suggest one potential molecular target for genetic strategies a imed at reducing cardiovascular risk.