Oxysterol binding protein induces upregulation of SREBP-1c and enhances 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).


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.


CONCLUSIONS
Our results demonstrate that OSBP regulates hepatic TG metabolism and suggest the involvement of OSBP in the insulin signaling pathways that control hepatic lipogenesis.
Yan
Daoguang
D
Department of Molecular Medicine, National Public Health Institute, Biomedicum, P.O.Box 104, FI-00251 Helsinki, Finland.
Lehto
Markku
M
Rasilainen
Laura
L
Metso
Jari
J
Ehnholm
Christian
C
Ylä-Herttuala
Seppo
S
Jauhiainen
Matti
M
Olkkonen
Vesa M
VM
D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D015243:Cholesterol, VLDL / Q000097:blood; D050556:Fatty Acid-Binding Proteins; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007328:Insulin / Q000378:metabolism; D050155:Lipogenesis / Q000502:physiology*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics*; D011817:Rabbits; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014280:Triglycerides / Q000096:biosynthesis; D015854:Up-Regulation; D000098825:Oxysterol Binding Proteins
D002352:Carrier Proteins; D015243:Cholesterol, VLDL; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; C471934:OSBPL3 protein, human; D012333:RNA, Messenger; D011987:Receptors, Steroid; D014280:Triglycerides; D000098825:Oxysterol Binding Proteins