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.
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 VLDLtriglycerides (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.
Authors: Anthony W G Burgett; Thomas B Poulsen; Kittikhun Wangkanont; D Ryan Anderson; Chikako Kikuchi; Kousei Shimada; Shuichi Okubo; Kevin C Fortner; Yoshihiro Mimaki; Minpei Kuroda; Jason P Murphy; David J Schwalb; Eugene C Petrella; Ivan Cornella-Taracido; Markus Schirle; John A Tallarico; Matthew D Shair Journal: Nat Chem Biol Date: 2011-08-07 Impact factor: 15.040
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Authors: Tim C M A Schreuder; Bart J Verwer; Carin M J van Nieuwkerk; Chris J J Mulder Journal: World J Gastroenterol Date: 2008-04-28 Impact factor: 5.742
Authors: Julia Perttilä; Krista Merikanto; Jussi Naukkarinen; Ida Surakka; Nicolas W Martin; Kimmo Tanhuanpää; Vinciane Grimard; Marja-Riitta Taskinen; Christoph Thiele; Veikko Salomaa; Antti Jula; Markus Perola; Ismo Virtanen; Leena Peltonen; Vesa M Olkkonen Journal: J Mol Med (Berl) Date: 2009-06-25 Impact factor: 4.599