PARTIAL TRANSFECTION OF LIVER WITH A SYNTHETIC CHOLESTEROL 7-ALPHA-HYDROXYLASE TRANSGENE IS SUFFICIENT TO STIMULATE THE REDUCTION OF CHOLESTEROL IN THE PLASMA OF HYPERCHOLESTEROLEMIC MICE

The effect of administering a synthetic transgene encoding cholesterol 7 alpha-hydroxylase (cyp7) on plasma cholesterol metabolism of intact mice was Investigated. The synthetic cyp7 transgene (Tg1) was constru cted by placing the cDNA sequence encoding the full-length cyp7 polype ptide under the control of a heavy metal inducible metallothionein pro moter. The transgene was complexed with asialoorosomucoid-polylysine c onjugate and introduced into mice via the tail vein. Cell marking expe riments using a beta-galactosidase (lacZ) transgene as a tag showed th at 5-10% of the liver can be transfected by this procedure. Administra tion of the Tg1 transgene to older hypercholesterolemic chow-fed mice resulted in about a 50% reduction of plasma cholesterol, regardless of whether or not transgene expression was induced by zinc treatment. In diet-induced hypercholesterolemic mice, the reduction (20%) in total plasma cholesterol was seen only when transgene expression was induced , and this reduction was due primarily to a decrease in non-high-densi ty lipoprotein cholesterol. The maximum reduction was evident al 6 day s after the introduction of the transgene and was no longer evident af ter 9 days. Introduction of the Tg1 transgene into young chow-fed mice had no effect on the already low levels of plasma cholesterol. Howeve r, compared with the no-transgene and lacZ transgene controls, the gal lbladder bile acid content of Tg1-treated mice was increased. The resu lts show that non-viral-mediated delivery of a synthetic transgene enc oding cyp7 to a subpopulation of hepatocytes in the liver of intact hy percholesterolemic mice is sufficient to facilitate the temporary redu ction of plasma cholesterol content.