出版社：American Society for Biochemistry and Molecular Biology
摘要：Our previous studies have demonstrated the activity of oncostatinM (OM) in stimulating the transcription of the human LDL receptor(LDLR) gene in HepG2 cells through a sterol-independent regulatorymechanism. The current studies were designed to determine whetherthis in vitro property of OM could be recapitulated in vivoto increase LDLR expression in cholesterol-loaded livers andconsequently decrease plasma levels of LDL-cholesterol (LDL-C)and total cholesterol (TC) using hypercholesterolemic hamstersas an experimental model. We show that administration of humanrecombinant OM for 7 days in hamsters fed a high-fat diet significantlyreduced plasma levels of TC, LDL-C, and triglyceride in dose-and time-dependent manners. This lipid-lowering effect was associatedwith increased hepatic LDLR mRNA expression, as determined byquantitative real-time RT-PCR. Additionally, hepatic fat storageand cholesterol content in the hypercholesterolemic animalswere substantially reduced by OM treatment. As a consequence,the increased aminotransferase levels in the high-fat diet-fedhamsters were normalized nearly to baseline values.
These results not only corroborate the in vitro finding of OMin the regulation of LDLR but also, for the first time, demonstratethat OM has a strong lipid-lowering effect under in vivo conditionsin which the levels of circulating LDL-C are high and liverLDLR transcription is repressed.Abbreviations: CT, threshold cycle; FC, free cholesterol; HFHC, high-fat and high-cholesterol; LDL-C, low density lipoprotein-cholesterol; LDLR, low density lipoprotein receptor, OM, oncostatin M; SIRE, sterol-independent regulatory element; SRE-1, sterol-regulatory element-1; SREBP, sterol-regulatory element binding protein; TC, total cholesterol; TG, triglyceride
Supplementary key words low density lipoprotein receptor • dyslipidemia • hepatosteatosis • sterol-independent regulatory element
