Human growth hormone increases Apo(a) expression in transgenic mice

Levels of Lp(a), an atherogenic lipoprotein that circulates in human plasma , are increased by the administration of growth hormone (GH). Many of the p hysiological effects of GH are mediated through insulin-like growth factor- 1 (IGF-1), but ironically, IGF-1 treatment of humans is associated with a f all in plasma Lp(a) levels. To glean insight into the mechanism responsible for the GH-associated increase in plasma levels of Lp(a), we administered recombinant human GH (rhGH) to mice expressing a 370-kb human genomic fragm ent containing the apo(a) gene, 40 kb of 5'-, and 200 kb of 3'-flanking seq uence [YAC-apo(a) transgenic mice]. The plasma levels of apo(a) and hepatic levels of apo(a) mRNA rose dramatically in the post-pubertal male mice in response to rhGH treatment. To determine whether the increase in plasma apo (a) was mediated by IGF-1, we treated castrated and noncastrated YAC-apo(a) transgenic mice with a continuous infusion of IGF-1 (100 mu g/d) for 2 wee ks, and plasma levels of apo(a) fell by approximate to 50%. Thus the effect s of rhGH and IGF-1 administration on plasma levels of apo(a) in the YAC-ap o(a) transgenic mice simulate those seen in humans. The coordinate changes in apo(a) mRNA and plasma levels of apo(a) in response to rhGH and IGF-1 st rongly suggest that these 2 hormones have independent effects on the transc ription of the apo(a) gene.