Systemic Effects of Postprandial Triglyceride-rich Lipoproteins on Macrovessels, Kidney, and Brain

The main focus of this doctoral research was to expand our understanding of postprandial triglyceride-rich lipoproteins (TGRL). Previous works in the Rutledge laboratory have demonstrated TGRL lipolysis products are pro-inflammatory and pro-apoptotic and that these processes might be mediated by transforming growth factor-beta (TGF-β). The studies presented here attempt to elucidate the cellular mechanisms through which this occurred and evaluate TGRL lipolysis products effects on other vascular related diseases. First, through my test with HAEC I deduced that reactive oxygen species (ROS) generated from TGRL lipolysis products treatment on HAEC likely activate TGF-β. Second, the effects of TGRL lipolysis products in renal system were explored with mouse and mesangial cell culture model. By infusing fluorescent marker with lipolysis products in mice, I have demonstrated significant albumin accumulation in glomerulus that resembles early signs of microalbuminuria. Western blot and realtime PCR analysis also demonstrated up-regulation of SMAD phosphorylation (a TGF-β effector) and inflammatory markers in the infused mice kidneys and mesangial cells. Finally, magnetic resonance imaging with rats showed that lipolysis products transiently perturbed the blood-brain barrier and increased permeability. These studies expanded the evidence implicating TGRL lipolysis products in vascular, renal, and cerebrovascular diseases.