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- Saliba-Gustafsson, P., et al.
(författare)
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Subclinical atherosclerosis and its progression are modulated by PLIN2 through a feed-forward loop between LXR and autophagy
- 2019
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 286:6, s. 660-675
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Tidskriftsartikel (refereegranskat)abstract
- Background Hyperlipidaemia is a major risk factor for cardiovascular disease, and atherosclerosis is the underlying cause of both myocardial infarction and stroke. We have previously shown that the Pro251 variant of perilipin-2 reduces plasma triglycerides and may therefore be beneficial to reduce atherosclerosis development. Objective We sought to delineate putative beneficial effects of the Pro251 variant of perlipin-2 on subclinical atherosclerosis and the mechanism by which it acts. Methods A pan-European cohort of high-risk individuals where carotid intima-media thickness has been assessed was adopted. Human primary monocyte-derived macrophages were prepared from whole blood from individuals recruited by perilipin-2 genotype or from buffy coats from the Karolinska University hospital blood central. Results The Pro251 variant of perilipin-2 is associated with decreased intima-media thickness at baseline and over 30 months of follow-up. Using human primary monocyte-derived macrophages from carriers of the beneficial Pro251 variant, we show that this variant increases autophagy activity, cholesterol efflux and a controlled inflammatory response. Through extensive mechanistic studies, we demonstrate that increase in autophagy activity is accompanied with an increase in liver-X-receptor (LXR) activity and that LXR and autophagy reciprocally activate each other in a feed-forward loop, regulated by CYP27A1 and 27OH-cholesterol. Conclusions For the first time, we show that perilipin-2 affects susceptibility to human atherosclerosis through activation of autophagy and stimulation of cholesterol efflux. We demonstrate that perilipin-2 modulates levels of the LXR ligand 27OH-cholesterol and initiates a feed-forward loop where LXR and autophagy reciprocally activate each other; the mechanism by which perilipin-2 exerts its beneficial effects on subclinical atherosclerosis.
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- Pippias, Maria, et al.
(författare)
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Long-term Kidney Transplant Outcomes in Primary Glomerulonephritis: Analysis From the ERA-EDTA Registry
- 2016
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Ingår i: Transplantation. - : LIPPINCOTT WILLIAMS & WILKINS. - 0041-1337 .- 1534-6080. ; 100:9, s. 1955-1962
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Tidskriftsartikel (refereegranskat)abstract
- Background We evaluated the 15-year kidney allograft survival in patients with primary glomerulonephritis and determined if the risk of graft loss varied with donor source within each glomerulonephritis group. Methods Using data from the European Renal Association-European Dialysis and Transplant Association Registry, Kaplan-Meier, competing risk, and Cox regression analyses were performed on adult, first kidney transplant recipients during 1991 to 2010 (n = 14 383). Follow-up was set to December 31, 2011. Adjustments for pretransplant dialysis duration, sex, country, and transplant era were made. Death-adjusted graft survival was assessed in patients with glomerulonephritis and compared with those with autosomal dominant polycystic kidney disease (ADPKD), in which the native kidney disease cannot recur. Additionally, death-adjusted graft survival was compared between living and deceased donor transplants within each glomerulonephritis group. Results All glomerulonephritides had a 15-year death-adjusted graft survival probability above 55%. The 15-year risk of death-adjusted graft failure compared to ADPKD ranged from 1.17 (95% confidence interval [95% CI], 1.05-1.31) for immunoglobulin A nephropathy to 2.09 (95% CI, 1.56-2.78) for membranoproliferative glomerulonephritis type II. The expected survival benefits of living over deceased donor transplants were not present in membranoproliferative glomerulonephritis type I (adjusted hazard ratios [HRa], 1.08; 95% CI, 0.73-1.60) or type II (HRa, 0.90; 95% CI, 0.32-2.52) but present in immunoglobulin A nephropathy (HRa, 0.74; 95% CI, 0.59-0.92), membranous nephropathy (HRa, 0.47; 95% CI, 0.29-0.75), and focal segmental glomerulosclerosis (HRa, 0.69; 95% CI, 0.45-1.06). Conclusions This large European study shows favorable long-term kidney graft survival in all primary glomerulonephritides, although this remains lower than graft survival in ADPKD, and confirms that the reluctance to use living donors in some primary glomerulonephritides remains unfounded. These data will further inform prospective renal transplant recipients and donors during pretransplant counselling.
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