title: Very low density lipoprotein receptor promotes adipocyte differentiation and mediates the proadipogenic effect of peroxisome proliferator-activated receptor gamma agonists.
abstract: Very low density lipoprotein receptor (VLDLR) is a member of the low density receptor family, expressed mostly in adipose tissue, heart, and skeletal muscles. VLDLR binds apolipoprotein-E-triglyceride-rich lipoproteins and plays a key role in lipid metabolism. In adipocytes, VLDLR expression increases with differentiation but it is not known whether it plays a role in the adipogenesis. Here we report that VLDLR expression in 3T3-L1 adipocytes is upregulated by PPARγ agonist 15-deoxy-delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) in dose- and time-dependant manners. Knockdown of peroxisome proliferator-activated receptor-γ (PPARγ) with siRNA abolished pioglitazone- and 15d-PGJ(2)-induced VLDLR expression and simultaneously reduced VLDL uptake in adipocytes. In addition, PPARγ-agonist treatment of control mouse adipocytes (vldlr(+/+)) enhanced adipogenesis and VLDL uptake concurrently with the induction of VLDLR expression. However, vldlr deficiency (vldlr(-/-)) significantly blunted the proadipogenic effects of PPARγ agonists. Sequence analysis revealed the presence of a putative PPARγ responsive sequence (PPRE) within the vldlr promoter, which is responsive to natural (15d-PGJ(2)) and synthetic (pioglitazone) PPARγ agonists. Reporter gene assays using serial deletion of the 5'-flanking region showed that this putative PPRE site induced promoter transactivation, while a site-targeted mutation abolished transactivation. Moreover, electrophoresis mobility shift assay (EMSA) and chromatic immunoprecipitation (ChIP) assays showed the specific binding of PPARγ to the PPRE sequence. Together, these results support a crucial function for VLDLR in adipocyte differentiation and mediation of the proadipogenic effect of PPARγ.
authors.affiliation: Department of Surgical Sciences, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Tao
authors.forename: Tahar
authors.initials: T
authors.lastname: Hajri
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000502:physiology; D050156:Adipogenesis / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000819:agonists*; D000077205:Pioglitazone; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: C477819:15-deoxyprostaglandin J2; D000960:Hypolipidemic Agents; D047495:PPAR gamma; D011973:Receptors, LDL; D045162:Thiazolidinediones; C036053:VLDL receptor; D015230:Prostaglandin D2; D000077205:Pioglitazone