title: Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production.
abstract: OBJECTIVE
  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 and lipoprotein metabolism.
  
  
  RESULTS
  The impact of PPAR-α 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-α/δ 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-α activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPAR-α activation decreased the cholesterol esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking, and reduced apolipoprotein-B secretion.
  
  
  CONCLUSIONS
  Peroxisome proliferator-activated receptor-α activation reduces cholesterol esterification, suppresses chylomicron, and increases HDL secretion by enterocytes. These results identify the intestine as a target organ of PPAR-α ligands with entero-hepatic tropism to reduce atherogenic dyslipidaemia.
authors: Université Lille Nord de France, Lille F-59000, France.
authors: Sophie
authors: S
authors: Colin
authors: Olivier
authors: O
authors: Briand
authors: Véronique
authors: V
authors: Touche
authors: Kristiaan
authors: K
authors: Wouters
authors: Morgane
authors: M
authors: Baron
authors: François
authors: F
authors: Pattou
authors: Rémy
authors: R
authors: Hanf
authors: Anne
authors: A
authors: Tailleux
authors: Giulia
authors: G
authors: Chinetti
authors: Bart
authors: B
authors: Staels
authors: Sophie
authors: S
authors: Lestavel
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism; D002087:Butyrates / Q000494:pharmacology; D018938:Caco-2 Cells; D002478:Cells, Cultured; D047188:Chalcones / Q000494:pharmacology; D020895:Enterocytes / Q000378:metabolism; D004951:Esterification / Q000502:physiology; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D007583:Jejunum / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000502:physiology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology
chemical_list: C585906:2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxo-1-propenyl)phenoxyl)-2-methylpropanoic acid; D001055:Apolipoproteins B; D002087:Butyrates; D047188:Chalcones; D005227:Fatty Acids; C453899:GW 7647; D008075:Lipoproteins, HDL; D047493:PPAR alpha; D010671:Phenylurea Compounds; D011422:Propionates