PPAR-β/δ activation promotes phospholipid transfer protein expression
2015; Elsevier BV; Volume: 94; Issue: 2 Linguagem: Inglês
10.1016/j.bcp.2015.01.016
ISSN1873-2968
AutoresKhouloud Chehaibi, Lídia Cedó, Jari Metso, Xavier Palomer, David Santos, Helena Quesada, Mohamed Naceur Slimane, Walter Wahli, Josep Julve, Manuel Vázquez‐Carrera, Matti Jauhiainen, Francisco Blanco‐Vaca, Joan Carles Escolà‐Gil,
Tópico(s)Drug Transport and Resistance Mechanisms
ResumoThe peroxisome proliferator-activated receptor (PPAR)-β/δ has emerged as a promising therapeutic target for treating dyslipidemia, including beneficial effects on HDL cholesterol (HDL-C). In the current study, we determined the effects of the PPAR-β/δ agonist GW0742 on HDL composition and the expression of liver HDL-related genes in mice and cultured human cells. The experiments were carried out in C57BL/6 wild-type, LDL receptor (LDLR)-deficient mice and PPAR-β/δ-deficient mice treated with GW0742 (10mg/kg/day) or a vehicle solution for 14 days. GW0742 upregulated liver phospholipid transfer protein (Pltp) gene expression and increased serum PLTP activity in mice. When given to wild-type mice, GW0742 significantly increased serum HDL-C and HDL phospholipids; GW0742 also raised serum potential to generate preβ-HDL formation. The GW0742-mediated effects on liver Pltp expression and serum enzyme activity were completely abolished in PPAR-β/δ-deficient mice. GW0742 also stimulated PLTP mRNA expression in mouse J774 macrophages, differentiated human THP-1 macrophages and human hepatoma Huh7. Collectively, our findings demonstrate a common transcriptional upregulation by GW0742-activated PPAR-β/δ of Pltp expression in cultured cells and in mouse liver resulting in enhanced serum PLTP activity. Our results also indicate that PPAR-β/δ activation may modulate PLTP-mediated preβ-HDL formation and macrophage cholesterol efflux.
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