Very low density lipoprotein receptor promotes adipocyte differentiation and mediates the proadipogenic effect of peroxisome proliferator-activated receptor gamma agonists

Biochem Pharmacol. 2011 Dec 15;82(12):1950-62. doi: 10.1016/j.bcp.2011.09.003. Epub 2011 Sep 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology*
  • Adipocytes / physiology
  • Adipogenesis / physiology*
  • Animals
  • Cell Differentiation
  • Gene Expression Regulation / drug effects*
  • Humans
  • Hypolipidemic Agents / pharmacology
  • Mice
  • PPAR gamma / agonists*
  • Pioglitazone
  • Prostaglandin D2 / analogs & derivatives
  • Prostaglandin D2 / pharmacology
  • Receptors, LDL / genetics
  • Receptors, LDL / metabolism*
  • Thiazolidinediones / pharmacology

Substances

  • 15-deoxyprostaglandin J2
  • Hypolipidemic Agents
  • PPAR gamma
  • Receptors, LDL
  • Thiazolidinediones
  • VLDL receptor
  • Prostaglandin D2
  • Pioglitazone