Cyclosporin A inhibits apolipoprotein AI gene expression

Abstract

Cyclosporin A (CsA), a calcineurin inhibitor, has been widely used as an immunosuppressant, and is known to induce hyperlipidemia and dyslipoproteinemia with low levels of high-density lipoprotein (HDL). Since apolipoprotein Al (apo Al) is a major protein component of HDL particles and reduction of apo Al results in low levels of HDL, we hypothesized that CsA inhibits apo Al gene expression contributing to its lipid effects. Therefore, we first measured the serum apo Al protein levels in rats with or without CsA treatment, and found that both serum apo Al protein and liver apo Al mRNA levels were significantly reduced in response to CsA treatment. In stably transfected Hep G2 cells harboring an apo Al-474-CAT reporter gene, we found that intracellular calcium mobilization by A23187 a calcium ionophore stimulated apo Al gene expression and the calcineurin inhibitors, CsA and FK605, selectively inhibited this stimulation. Therefore, we conclude that activation of the calcineurin pathway by intracellular calcium mobilization stimulates apo Al gene expression and calcineurin inhibition by CsA results in reduced apo Al gene expression. © 2006 Society for Endocrinology.