In vivo activities of cytokine oncostatin M in the regulation of plasma lipid levels

Abstract

Our previous studies have demonstrated the activity of oncostatin M (OM) in stimulating the transcription of the human LDL receptor (LDLR) gene in HepG2 cells through a sterol-independent regulatory mechanism. The current studies were designed to determine whether this in vitro property of OM could be recapitulated in vivo to increase LDLR expression in cholesterol-loaded livers and consequently decrease plasma levels of LDL-cholesterol (LDL-C) and total cholesterol (TC) using hypercholesterolemic hamsters as an experimental model. We show that administration of human recombinant OM for 7 days in hamsters fed a high-fat diet significantly reduced plasma levels of TC, LDL-C, and triglyceride in dose- and time-dependent manners. This lipid-lowering effect was associated with increased hepatic LDLR mRNA expression, as determined by quantitative real-time RT-PCR. Additionally, hepatic fat storage and cholesterol content in the hypercholesterolemic animals were substantially reduced by OM treatment. As a consequence, the increased aminotransferase levels in the high-fat diet-fed hamsters were normalized nearly to baseline values. These results not only corroborate the in vitro finding of OM in the regulation of LDLR but also, for the first time, demonstrate that OM has a strong lipid-lowering effect under in vivo conditions in which the levels of circulating LDL-C are high and liver LDLR transcription is repressed.