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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1108.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Oxysterol Binding Protein Induces Upregulation of SREBP-1c and Enhances Hepatic Lipogenesis

Daoguang Yan; Markku Lehto; Laura Rasilainen; Jari Metso; Christian Ehnholm; Seppo Ylä-Herttuala; Matti Jauhiainen; Vesa M. Olkkonen

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.

Correspondence to Vesa M. Olkkonen, Department of Molecular Medicine, National Public Health Institute, Biomedicum, P.O.Box 104, FI-00251 Helsinki, Finland. 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.

Overexpression of OSBP in mouse liver induced an increase of VLDL and liver triglycerides, upregulation of hepatic SREBP-1c, and reduction of ERK phosphorylation. Silencing of OSBP suppressed SREBP-1c induction by insulin and resulted in reduction of triglyceride synthesis, demonstrating a new role of OSBP in regulation of hepatic lipogenesis.

Key Words: OSBP • oxysterol binding protein • lipogenesis • liver • SREBP-1c • triglyceride synthesis • VLDL secretion

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