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Activation of intestinal peroxisome proliferator-activated receptor-? increases high-density lipoprotein production.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-? is a transcription factor controlling lipid metabolism in liver, heart, muscle, and macrophages. Peroxisome proliferator-activated receptor-? activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver. However, the intestine expresses PPAR-?, produces HDL and chylomicrons, and is exposed to diet-derived PPAR-? ligands. Therefore, we examined the effects of PPAR-? activation on intestinal lipid and lipoprotein metabolism.The impact of PPAR-? activation was evaluated in term of HDL-related gene expression in mice, ex vivo in human jejunal biopsies and in Caco-2/TC7 cells. Apolipoprotein-AI/HDL secretion, cholesterol esterification, and trafficking were also studied in vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty acid oxidation genes, treatment with the dual PPAR-?/? ligand GFT505 resulted in a more pronounced increase in plasma HDL compared with fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL production genes such as apolipoprotein-AI and ATP-binding cassette A1 transporter in murine intestines. A similar increase was observed upon PPAR-? activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPAR-? activation decreased the cholesterol esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking, and reduced apolipoprotein-B secretion.Peroxisome proliferator-activated receptor-? activation reduces cholesterol esterification, suppresses chylomicron, and increases HDL secretion by enterocytes. These results identify the intestine as a target organ of PPAR-? ligands with entero-hepatic tropism to reduce atherogenic dyslipidaemia.

SUBMITTER: Colin S

PROVIDER: S-EPMC3984589 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production.

Colin Sophie S Briand Olivier O Touche Véronique V Wouters Kristiaan K Baron Morgane M Pattou François F Hanf Rémy R Tailleux Anne A Chinetti Giulia G Staels Bart B Lestavel Sophie S

European heart journal 20120726 32

<h4>Aims</h4>Peroxisome proliferator-activated receptor (PPAR)-α is a transcription factor controlling lipid metabolism in liver, heart, muscle, and macrophages. Peroxisome proliferator-activated receptor-α activation increases plasma HDL cholesterol and exerts hypotriglyceridaemic actions via the liver. However, the intestine expresses PPAR-α, produces HDL and chylomicrons, and is exposed to diet-derived PPAR-α ligands. Therefore, we examined the effects of PPAR-α activation on intestinal lipid ...[more]

PMID: 22843443

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Project description:Apolipoprotein E (apoE) and its receptor, very low density lipoprotein receptor (VLDLR), are involved in fat accumulation in adipocytes. Here, we investigated the effect of a peroxisome proliferator-activated receptor (PPAR) gamma agonist, rosiglitazone, on regulation of VLDLR expression both in white adipose tissue (WAT) of obese mice and in cultured adipocytes. Furthermore, to determine whether rosiglitazone directly regulates transcription of the VLDLR gene, we carried out luciferase assay with a reporter gene containing mouse VLDLR promoter region, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay. Four-day treatment with rosiglitazone increased the expression of VLDLR in WAT of ob/ob mice. Moreover, rosiglitazone increased the expression of VLDLR in cultured adipocytes. The PPAR-responsive element (PPRE)-directed mutagenesis analyses revealed that the PPRE motif in the VLDLR promoter region plays a significant role in transcriptional activation of the VLDLR gene in adipocytes. In addition, electrophoretic mobility shift assay and chromatin immunoprecipitation assay demonstrated that endogenous PPARgamma directly binds to this functional PPRE motif in the VLDLR promoter region. We also investigated the effects of rosiglitazone on insulin sensitivity and lipid accumulation in both ob/ob mice and apoE-deficient ob/ob mice. Rosiglitazone ameliorated insulin sensitivity in both ob/ob mice and apoE-deficient ob/ob mice, possibly through decreasing the expression of monocyte chemoattractant protein-1 (MCP-1), increasing the expression of superoxide dismutase 1 (SOD1) in WAT, and increasing plasma adiponectin concentration. In ob/ob mice, body weight and WAT weight were significantly higher in the mice treated with rosiglitazone than those treated with vehicle. However, in apoE-deficient ob/ob mice, no significant difference in body weight or WAT weight was observed between the vehicle-treated group and the rosiglitazone-treated group. Moreover, rosiglitazone did not increase body weight and WAT weight in VLDLR-deficient mice. These findings indicate that rosiglitazone directly increases VLDLR expression, thereby enhancing apoE-VLDLR-dependent lipid accumulation in adipocytes.

Dataset Information

Activation of intestinal peroxisome proliferator-activated receptor-? increases high-density lipoprotein production.

Publications

Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production.

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