title: A novel peroxisome proliferator response element modulates hepatic low-density lipoprotein receptor gene transcription in response to PPARδ activation.
abstract: The hepatic expression of low-density lipoprotein (LDL) receptor (LDLR) gene is regulated primarily at the transcriptional level by a sterol-regulatory element (SRE) in its proximal promoter region which is the site of action of SRE-binding protein 2 (SREBP2). However whether additional cis-regulatory elements contribute to LDLR transcription has not been fully explored. We investigated the function of a putative peroxisome proliferator-activated receptor (PPAR)-response element (PPRE) sequence motif located at -768 to -752 bases upstream of the transcription start site of human LDLR gene in response to PPARδ activation. Promoter luciferase reporter analyses showed that treating HepG2 cells with PPARδ agonist L165041 markedly increased the activity of a full-length LDLR promoter construct (pLDLR-1192) without any effects on the shorter promoter reporter pLDLR-234 that contains only the core regulatory elements SRE-1 and SP1 sites. Importantly, mutation of the PPRE sequence greatly attenuated the induction of the full-length LDLR promoter activity by L165041 without affecting rosuvastatin (RSV)-mediated transactivation. EMSA and ChIP assay further confirmed the binding of PPARδ to the LDLR-PPRE site. Treating HepG2 cells with L165041 elevated the mRNA and protein expressions of LDLR without affecting the LDLR mRNA decay rate. The induction of LDLR expression by PPARδ agonist was further observed in liver tissue of mice and hamsters treated with L165041. Altogether, our studies identify a novel PPRE-mediated regulatory mechanism for LDLR transcription and suggest that combined treatment of statin with PPARδ agonists may have advantageous effects on LDLR expression.
authors.affiliation: Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, U.S.A.
authors.forename: Vikram R
authors.initials: VR
authors.lastname: Shende
authors.affiliation: Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, U.S.A.
authors.forename: Amar Bahadur
authors.initials: AB
authors.lastname: Singh
authors.affiliation: Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, U.S.A. Jingwen.Liu@va.gov.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Liu
mesh_terms: D000818:Animals; D006224:Cricetinae; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D047494:PPAR delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000096:biosynthesis* / Q000235:genetics; D020218:Response Elements / Q000502:physiology*; D000068718:Rosuvastatin Calcium / Q000494:pharmacology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*
chemical_list: C573412:LDLR protein, human; D047494:PPAR delta; D011973:Receptors, LDL; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D000068718:Rosuvastatin Calcium
keywords: low-density lipoprotein (LDL) receptor; peroxisome proliferator-activated receptor δ (PPARδ); peroxisome proliferator-activated receptor-response element (PPRE); statin; sterol-regulatory element-binding protein 2 (SREBP2); transcriptional regulation