ROLE OF ABNORMAL LIPOPROTEINS IN ATHEROSCLEROSIS AND RENAL DISEASE IN LCAT DEFICIENCY
Creators: name: OSSOLI, ALICE FEDERICA
Publisher: name: Universit� degli Studi di Milano
Year: 2014

description: The lecithin:cholesterol acyltransferase (LCAT) is the unique enzyme in human plasma responsible for the synthesis of cholesteryl esters and plays a critical role in high density lipoprotein (HDL) metabolism. Genetic LCAT deficiency is a rare metabolic disorder characterized by abnormal plasma lipoprotein profile characterized by low HDL level, mainly small discoidal pre-beta particles, and by presence of LpX, an abnormal lipoprotein usually absent in normal plasma and detectable only in some pathological cases. The impact of LCAT on human atherogenesis is controversial. Furthermore, the cause of renal disease, the major cause of morbidity and mortality in LCAT deficient patients, is poorly understood. Aim of my project was to analyze the peculiar characteristic of abnormal lipoprotein accumulated in LCAT deficient subjects and evaluate LCAT role in atherosclerosis and renal disease. To analyze LCAT role in atherosclerosis in vitro and in vivo studies were performed. HDL isolated from LCAT deficient carriers showed peculiar antiinflammatory (VCAM-1 inhibition) and vasoactive properties (nitric oxide production) in modulating cell endothelial homeostasis, on the contrary in vivo studies on mouse model that overexpress LCAT showed increased expression in aorta of genes involved in inflammation and vasoconstriction. The in vitro and in vivo data described in the present thesis suggest that the specific HDL subpopulations which accumulate in LCAT deficiency , mainly small discoidal pre-beta HDL, are more effective in maintaining endothelial homeostasis than control HDL. On the contrary, the large HDL formed when LCAT is overexpressed are less efficient than control HDL in regulating vascular tone and inflammation. The in vitro data were also confirmed by analysis in human. Indeed, despite the low HDL-cholesterol levels in plasma, LCAT deficient subjects showed plasmatic levels of soluble cell adhesion molecules and flow mediated vasodilation comparable to control subjects with HDL-cholesterol levels in normal range. The second objective of the present study was to evaluate the role of abnormal lipoproteins present in plasma of carriers of LCAT deficiency in renal injury. The possible implication of LpX in kidney injury was analyzed by testing LpX on renal cells and in mice. Sera from LCAT deficient carriers showed an higher capacity to stimulate inflammation, oxidative stress and apoptosis in tubular cells. Mesangial and podocytes cells are able to internalize LpX, but this particle localizes preferentially in tubular compartment of kidney when it is injected in LCAT knockout mice. The acute and chronic exposure of LpX leads to a significant increase of microalbumin/creatinine ratio in urine of LCAT knockout mice. In these mice, after chronic LpX exposure, up regulation of a large set of genes involved in nephrotoxic pathway was observed. In summary, in this work was shown that LpX is involved in renal disease pathogenesis with a non-specific pathway that allows mesangial, podocyte and tubular cell injury and the lack of LCAT enzyme is clearly crucial for kidney injury mediated by LpX.