Synergistic activation of human LDL receptor expression by SCAP ligand and cytokine oncostatin M.

ABSTRACT

OBJECTIVE: A recent study identified a new class of compounds designated as the sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) ligands that putatively bind to SCAP, leading to increased LDL receptor (LDLR) expression. In this study, we examined the effects of SCAP ligand GW707 in comparison with lovastatin and cytokine oncostatin M (OM) on the regulation of LDLR expression in cultured HepG2 cells. METHODS AND RESULTS: Our studies uncovered several new features that distinguish SCAP ligand from lovastatin, a classic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and from OM, which utilize an SREBP-independent regulatory pathway. We show that the induction of LDLR mRNA expression by GW707 is not affected by intracellular cholesterol but is completely abolished by blocking de novo protein synthesis. Moreover, the effects of GW707 but not lovastatin on LDLR promoter activity, mRNA expression, and uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanin perchlorate-LDL are markedly enhanced by OM. We further demonstrate that the amounts of the mature form of SREBP-2 translocated to the nucleus under GW707 treatment are increased by costimulating cells with OM. CONCLUSIONS: Our studies provide the first evidence that higher levels of LDLR expression and function can be achieved through simultaneous stimulation of the SREBP-dependent and SREBP-independent pathways, suggesting a strategy to develop an adjunct therapeutic intervention utilizing both pathways.