RESUMO
Peroxisome proliferator-activated receptor δ (PPARδ) is a ligand-activated transcription factor that has an important role in lipid metabolism. Activation of PPARδ stimulates fatty acid oxidation in adipose tissue and skeletal muscle and improves dyslipidemia in mice and humans. PPARδ is highly expressed in the intestinal tract but its physiological function in this organ is not known. Using mice with an intestinal epithelial cell-specific deletion of PPARδ, we show that intestinal PPARδ protects against diet-induced obesity, insulin resistance and dyslipidemia. Furthermore, absence of intestinal PPARδ abolished the ability of PPARδ agonist GW501516 to increase plasma levels of HDL-cholesterol. Together, our findings show that intestinal PPARδ is important in maintaining metabolic homeostasis and suggest that intestinal-specific activation of PPARδ could be a therapeutic approach for treatment of the metabolic syndrome and dyslipidemia, while avoiding systemic toxicity.
Assuntos
Dislipidemias/metabolismo , Resistência à Insulina , Mucosa Intestinal/metabolismo , Obesidade/metabolismo , PPAR delta/genética , Animais , HDL-Colesterol/sangue , Dislipidemias/genética , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , PPAR delta/agonistas , PPAR delta/metabolismoRESUMO
Pex14 was initially identified as a peroxisomal membrane protein that is involved in docking of the soluble receptor proteins Pex5 and Pex7, which are required for import of PTS1- or PTS2-containing peroxisomal matrix proteins. However, Hansenula polymorpha Pex14 is also required for selective degradation of peroxisomes (pexophagy). Previously we showed that Pex1, Pex4, Pex6 and Pex8 are not required for this process. Here we show that also in the absence of various other peroxins, namely Pex2, Pex10, Pex12, Pex13 and Pex17, pexophagy can normally occur. These peroxins are, like Pex14, components of the peroxisomal translocon. Our data confirm that Pex14 is the sole peroxin that has a unique dual function in two apparent opposite processes, namely peroxisome formation and selective degradation.