ABSTRACT
The very low-density lipoprotein receptor (VLDLR) plays an important function in the control of serum triglycerides and in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the role of peroxisome proliferator-activated receptor (PPAR)ß/δ activation in hepatic VLDLR regulation. Treatment of mice fed a high-fat diet with the PPARß/δ agonist GW501516 increased the hepatic expression of Vldlr. Similarly, exposure of human Huh-7 hepatocytes to GW501516 increased the expression of VLDLR and triglyceride accumulation, the latter being prevented by VLDLR knockdown. Finally, treatment with another PPARß/δ agonist increased VLDLR levels in the liver of wild-type mice, but not PPARß/δ-deficient mice, confirming the regulation of hepatic VLDLR by this nuclear receptor. Our results suggest that upregulation of hepatic VLDLR by PPARß/δ agonists might contribute to the hypolipidemic effect of these drugs by increasing lipoprotein delivery to the liver. Overall, these findings provide new effects by which PPARß/δ regulate VLDLR levels and may influence serum triglyceride levels and NAFLD development
El receptor de las lipoproteínas de muy baja densidad (VLDLR) desempeña una función muy importante en el control de los niveles de triglicéridos séricos y en el desarrollo de la enfermedad del hígado graso no alcohólico (EHGNA). En este estudio hemos investigado el papel de la activación del receptor activado por los proliferadores peroxisómicos (PPAR)ß/δ en la regulación hepática del VLDLR. El tratamiento de ratones alimentados con una dieta rica en grasas con el agonista PPARß/δ GW501516 aumentó la expresión hepática de Vldlr. Asimismo, la exposición de hepatocitos humanos Huh-7 a GW501516 aumentó la expresión de VLDLR y la acumulación de triglicéridos, siendo este ultimo aumento evitado por el knockdown de VLDLR. Finalmente, el tratamiento con otro agonista PPARß/δ incrementó los niveles de VLDLR en el hígado de ratones wild-type, pero no en el de ratones deficientes en PPARß/δ, confirmando la regulación del VLDLR hepático por este receptor. En conjunto, nuestros resultados proporcionan un nuevo efecto por el que PPARß/δ regula los niveles de VLDLR y puede influenciar los niveles de triglicéridos séricos así como el desarrollo de la EHGNA
Subject(s)
Animals , Mice , PPAR-beta/drug effects , PPAR-beta/metabolism , Hepatocytes/metabolism , Lipoproteins, VLDL/agonists , Lipoproteins, VLDL/metabolism , Dietary Fats , Triglycerides/metabolism , Blotting, Western , Analysis of Variance , PPAR-beta/pharmacologyABSTRACT
Plasma VLDL accumulation in Gram-negative sepsis is partly ascribed to an increased hepatic VLDL production driven by pro-inflammatory cytokines. We previously showed that hepatocytes of the Kupffer cell (KC)-rich periportal area are major contributors to enhanced VLDL production in lipopolysaccharide (LPS)-injected rats. However, it remains to be established whether KC generated products directly affect the number (apoB) and composition of secreted VLDL. Using rat primary cells, we show here that hepatocytes respond to stimulation by soluble mediators released by LPS-stimulated Kupffer cells with enhanced secretion of apoB and triglycerides in phospholipid-rich VLDL particles. Unstimulated KC products also augmented the secretion of normal VLDL, doubling apoB mRNA abundance. IL-1beta treatment resulted in concentration-dependent increases of hepatocyte apoB mRNA and protein secretion, increases that were greater, but not additive, when combined with IL-6 and TNF-alpha. Lipid secretion and MTP mRNA levels were unaffected by cytokines. In summary: (i) enhanced secretion of phospholipid-rich VLDL particles is a net hepatocyte response to LPS-stimulated KC products, which gives a clue about the local role of Kupffer cells in septic dyslipidemia induction; and (ii) pro-inflammatory cytokines act redundantly to enhance apoB secretion involving translational apoB up-regulation, but other humoral components or KC mediators are necessary to accomplish increased lipid association.
