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

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Graphical abstractVery 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-delta12,14-prostaglandin J2 (15d-PGJ2) in dose- and time-dependant manners. Knockdown of peroxisome proliferator-activated receptor-γ (PPARγ) with siRNA abolished pioglitazone- and 15d-PGJ2-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-PGJ2) 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.

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