Journal
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
Volume 27, Issue 10, Pages 2198-2205Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.107.148429
Keywords
acyl-CoA synthetase; oncostatin M; hypertriglyceridemia; ERK; fatty acid beta-oxidation
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Funding
- NCCIH NIH HHS [1R01 AT002543-01A1] Funding Source: Medline
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Objective-In our previous studies that examined in vivo activities of oncostatin M (OM) in upregulation of hepatic LDL receptor (LDLR) expression, we observed reductions of LDL-cholesterol and triglyceride (TG) levels in OM-treated hyperlipidemic hamsters. Interestingly, the OM effect of lowering plasma TG was more pronounced than LDL-cholesterol reduction, suggesting additional LDLR-independent actions. Here, we investigated mechanisms underlying the direct TG-lowering effect of OM. Methods and Results-We demonstrate that OM activates transcription of long-chain acyl-coenzymeA (CoA) synthetase isoforms 3 and 5 (ACSL3, ACSL5) in HepG2 cells through the extracellular signal-regulated kinase (ERK) signaling pathway. Increased acyl-CoA synthetase activities in OM-stimulated HepG2 cells and in livers of OM-treated hamsters are associated with decreased TG accumulation and increased fatty acid beta-oxidation. We further show that overexpression of ACSL3 or ACSL5 alone in the absence of OM led to fatty acid partitioning into beta-oxidation. Importantly, we demonstrate that transfection of siRNAs targeted to ACSL3 and ACSL5 abrogated the enhancing effect of OM on fatty acid oxidation in HepG2 cells. Conclusions-These new findings identify ACSL3 and ACSL5 as OM-regulated genes that function in fatty acid metabolism and suggest a novel cellular mechanism by which OM directly lowers the plasma TG in hyperlipidemic animals through stimulating the transcription of ACSL specific isoforms in the liver.
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