on February 15, 2007
Published online before print February 15, 2007, doi: 10.1161/ATVBAHA.106.138545
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Submitted on October 6, 2006
Accepted on January 23, 2007
Oxysterol Binding Protein Induces Upregulation of SREBP-1c and Enhances Hepatic Lipogenesis
Daoguang Yan ;
From the Department of Molecular Medicine (D.Y., M.L., L.R., J.M., C.E., M.J., V.M.O.), National Public Health Institute, Biomedicum, Helsinki; and A.I. Virtanen Institute (S.Y.-H.), University of Kuopio, Finland.
* To whom correspondence should be addressed. E-mail: vesa.olkkonen{at}ktl.fi.
Background--Oxysterol binding protein (OSBP) has previously been implicated as a sterol sensor that regulates sphingomyelin synthesis and the activity of extracellular signal-regulated kinases (ERK).
Methods and Results--We determined the effects of adenovirus-mediated hepatic overexpression of OSBP and its homologues ORP1L and ORP3 on mouse serum lipids. Whereas ORP1L and ORP3 had no effect on serum lipids, OSBP induced a marked increase of VLDL triglycerides (TG). Also, the liver tissue TG were elevated in the AdOSBP-injected mice, and their TG secretion rate was increased by 70%. The messenger RNAs for enzymes of fatty acid synthesis and their transcriptional regulator, SREBP-1c, as well as the Insig-1 mRNA, were upregulated two-fold in the OSBP-expressing livers. No change occurred in the messages of liver X receptor target genes ABCA1, ABCG5, and CYP7A1, and the Insig-2a mRNA was reduced. The phosphorylation of ERK was decreased in AdOSBP-infected liver and cultured hepatocytes. Importantly, silencing of OSBP in hepatocytes suppressed the induction of SREBP1-c by insulin and resulted in a reduction of TG synthesis.
Conclusion--Our results demonstrate that OSBP regulates hepatic TG metabolism and suggest the involvement of OSBP in the insulin signaling pathways that control hepatic lipogenesis.
Key words: OSBP • oxysterol binding protein • lipogenesis • liver • SREBP-1c • triglyceride synthesis • VLDL secretion
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