Published online before print February 15, 2007, doi: 10.1161/ATVBAHA.106.138545
© 2007 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Oxysterol Binding Protein Induces Upregulation of SREBP-1c and Enhances Hepatic Lipogenesis
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
This article has been cited by other articles:
 |
|
 |
|
  M. Ngo and N. D. Ridgway Oxysterol Binding Protein-related Protein 9 (ORP9) Is a Cholesterol Transfer Protein That Regulates Golgi Structure and Function Mol. Biol. Cell, March 1, 2009; 20(5): 1388 - 1399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Payre, P. de Medina, N. Boubekeur, L. Mhamdi, J. Bertrand-Michel, F. Terce, I. Fourquaux, D. Goudouneche, M. Record, M. Poirot, et al. Microsomal antiestrogen-binding site ligands induce growth control and differentiation of human breast cancer cells through the modulation of cholesterol metabolism Mol. Cancer Ther., December 1, 2008; 7(12): 3707 - 3718. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Leung, S. Cases, and T. H. Vu P311 functions in an alternative pathway of lipid accumulation that is induced by retinoic acid J. Cell Sci., August 15, 2008; 121(16): 2751 - 2758. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Bowden and N. D. Ridgway OSBP Negatively Regulates ABCA1 Protein Stability J. Biol. Chem., June 27, 2008; 283(26): 18210 - 18217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P.-Y. Wang, J. Weng, S. Lee, and R. G. W. Anderson The N Terminus Controls Sterol Binding while the C Terminus Regulates the Scaffolding Function of OSBP J. Biol. Chem., March 21, 2008; 283(12): 8034 - 8045. [Abstract] [Full Text] [PDF]
|
|