Submitted on October 27, 2004
Revised on February 1, 2005
Accepted on February 28, 2005
In vivo activities of cytokine oncostatin M in regulation of plasma lipid levels
Weijia Kong, Parveen Ibidi, Fredric B. Kraemer, Jian-Dong Jiang, and Jingwen Liu
Research, VA Palo Alto Health Care System (154P), Palo Alto, CA 94304
Corresponding Author: Jingwen.Liu{at}med.va.gov
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 lower plasma levels of LDL-cholesterol and total cholesterol by 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 total cholesterol, LDL-cholesterol, and triglyceride in dose- and time-dependent manners. This lipid lowering effect was associated with an elevated hepatic LDLR mRNA expression determined by quantitative real-time RT-PCR. Additionally, the hepatic fat storage and cholesterol content in the hypercholesterolemic animals were substantially reduced by OM treatment. As a consequence, the elevated aminotransferase levels in the high fat diet fed hamsters were normalized nearly to the 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 where levels of circulating LDL-c are high and liver LDLR transcription is repressed.
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