Synergistic activation of human LDL receptor expression by SCAP ligand and cytokine oncostatin M.
OBJECTIVE
A recent study identified a new class of compounds designated as the sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) ligands that putatively bind to SCAP, leading to increased LDL receptor (LDLR) expression. In this study, we examined the effects of SCAP ligand GW707 in comparison with lovastatin and cytokine oncostatin M (OM) on the regulation of LDLR expression in cultured HepG2 cells.


RESULTS
Our studies uncovered several new features that distinguish SCAP ligand from lovastatin, a classic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, and from OM, which utilize an SREBP-independent regulatory pathway. We show that the induction of LDLR mRNA expression by GW707 is not affected by intracellular cholesterol but is completely abolished by blocking de novo protein synthesis. Moreover, the effects of GW707 but not lovastatin on LDLR promoter activity, mRNA expression, and uptake of 1,1'-dioctadecyl-3,3,3',3'-tetramethyl-indocarbocyanin perchlorate-LDL are markedly enhanced by OM. We further demonstrate that the amounts of the mature form of SREBP-2 translocated to the nucleus under GW707 treatment are increased by costimulating cells with OM.


CONCLUSIONS
Our studies provide the first evidence that higher levels of LDLR expression and function can be achieved through simultaneous stimulation of the SREBP-dependent and SREBP-independent pathways, suggesting a strategy to develop an adjunct therapeutic intervention utilizing both pathways.
Liu
Jingwen
J
VA Palo Alto Health Care System, Palo Alto, Calif 94304, USA. Jingwen.Liu@med.va.gov
Zhang
Fang
F
Li
Cong
C
Lin
Meihong
M
Briggs
Michael R
MR
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000502:physiology; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007700:Kinetics; D008024:Ligands; D008148:Lovastatin / Q000378:metabolism / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism* / Q000494:pharmacology; D053683:Oncostatin M; D010452:Peptide Biosynthesis / Q000187:drug effects; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014407:Tumor Cells, Cultured
D022762:CCAAT-Enhancer-Binding Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; C442817:GW 707; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; C508351:OSM protein, human; D010455:Peptides; D012333:RNA, Messenger; D011973:Receptors, LDL; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; C102196:SREBP cleavage-activating protein; D013256:Steroids; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D053683:Oncostatin M; D008148:Lovastatin