RESUMEN
Feeding and the circadian system regulate lipid absorption and metabolism, and the expression of enzymes involved in lipid metabolism is believed to be directly controlled by the clock system. To investigate the interaction between the lipid metabolism system and the circadian system, we analyzed the effect of a CLOCK/BMAL1 heterodimer on the transcriptional regulation of PPAR-controlled genes through PPAR response elements (PPREs). Transcription of acyl-CoA oxidase, cellular retinol binding protein II (CRBPII), and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) synthase was altered by CLOCK/BMAL1, and transcriptional activity via PPRE by PPARs/RXRalpha was enhanced by CLOCK/BMAL1 and/or by PPARs ligand/activators. We also found that CLOCK/BMAL1-mediated transcription of period (PER) and cryptochrome (CRY) was modulated by PPARalpha/RXRalpha. These results suggest that there may be crosstalk between the PPARs/RXRalpha-regulated system and the CLOCK/BMAL1-regulated system.
RESUMEN
Intestinal alkaline phosphatase (IAP) is involved in the process of fat absorption, a conclusion confirmed by an altered lipid transport and a faster body weight gain from 10 to 30 wk in both male and female mice with a homozygous null mutation of the IAP coding gene (Akp3(-/-) mice). This study was aimed to delineate morphologically and quantitatively the accelerated lipid absorption in male Akp3(-/-) mice. Feeding a corn oil bolus produced an earlier peak of triacylglycerol in serum (2 vs. 4 h for Akp3(-/-) and wild-type mice, respectively) and an approximately twofold increase in serum triacylglycerol concentration in Akp3(-/-) mice injected with a lipolysis inhibitor, Triton WR-1339. A corn oil load induced the threefold enlargement of the Golgi vacuoles in male wild-type mice but not in Akp3(-/-) mice, indicating that absorbed lipids rarely reached the Golgi complex and that the transcytosis of lipid droplets does not follow the normal pathway in male Akp3(-/-) mice. Force feeding an exaggerated fat intake by a 30% fat chow for 10 wk induced obesity in both male Akp3(-/-) and wild-type mice, and therefore no phenotypic difference was observed between the two. On the other hand, the forced high-fat chow induced an 18% greater body weight gain, hepatic steatosis, and visceral fat accumulation in female Akp3(-/-) mice but not in female wild-type controls. These results provide further evidence that IAP is involved in the regulation of the lipid absorption process and that its absence leads to progressive metabolic abnormalities in certain fat-forced conditions.
Asunto(s)
Fosfatasa Alcalina/genética , Hígado Graso/etiología , Absorción Intestinal/efectos de los fármacos , Intestino Delgado/enzimología , Grasa Intraabdominal/crecimiento & desarrollo , Metabolismo de los Lípidos/efectos de los fármacos , Fosfatasa Alcalina/antagonistas & inhibidores , Fosfatasa Alcalina/metabolismo , Animales , Grasas de la Dieta/administración & dosificación , Femenino , Grasa Intraabdominal/efectos de los fármacos , Lipoproteína Lipasa/antagonistas & inhibidores , Masculino , Ratones , Polietilenglicoles/farmacología , Triglicéridos/sangreRESUMEN
Apoptosis in human umbilical vein endothelial cells (HUVECs) was prevented by transfection with the gene for the human full-length peroxisome proliferator-activated receptor alpha (PPARalpha), or acyl-coenzyme A synthetase (AcylCS) into HUVECs. In contrast, ligands/activators of PPARgamma 1 induced apoptosis by a cytochrome c-dependent mechanism in HUVECs transfected with human full-length PPARgamma 1, but not in hepatocytes. Co-transfection of PPARgamma 1 and PPARalpha protected the HUVEC apoptosis. The results suggest that the apoptosis of endothelial cells may be mediated by genes of PPARgamma1 and PPARalpha.