Elucidation of an SRE-1/SREBP-independent cellular pathway for LDL-receptor regulation: from the cell surface to the nucleus.

Reduction in blood levels of low-density lipoprotein (LDL) cholesterol lowers the risk of coronary heart disease. The elucidation of cellular pathways that control LDL-receptor expression through a cholesterol-mediated negative feedback mechanism has provided a crucial molecular basis for the development and clinical applications of statins in the treatment of hypercholesterolemia. The characterization of signaling transduction pathways elicited by cytokine oncostatin M (OM) in liver cells has revealed a novel cellular pathway that activates LDL-receptor transcription independent of intracellular levels of cholesterol and sterol-regulatory element binding proteins. This transcriptional activation is achieved through interactions of the sterol-independent regulatory element of LDL-receptor promoter and transcription factors Egr1 and c/EBPbeta, and is dependent upon the activation of the extracellular signal-regulated kinase signaling cascade by OM. In vivo OM administration in hyperlipidemic animals reduces circulating cholesterol and prevents lipid accumulation in the liver. Exploring this sterol-independent cellular pathway may lead to new therapeutic advances.