Analysis of glomerulosclerosis and atherosclerosis in lecithin cholesterolacyltransferase-deficient mice

To evaluate the biochemical and molecular mechanisms leading to glomerulosc lerosis and the variable development of atherosclerosis in patients with fa milial lecithin cholesterol acyl transferase (LCAT) deficiency, we generate d LCAT knockout (KO) mice and cross-bred them with apolipoprotein (apo) E K O, low density lipoprotein receptor (LDLr) KO, and cholesteryl ester transf er protein transgenic mice, LCAT-KO mice had normochromic normocytic anemia with increased reticulocyte and target cell counts as well as decreased re d blood cell osmotic fragility. A subset of LCAT-KO mice accumulated lipopr otein X and developed proteinuria and glomerulosclerosis characterized by m esangial cell proliferation, sclerosis, lipid accumulation, and deposition of electron dense material throughout the glomeruli. LCAT deficiency reduce d the plasma high density lipoprotein (HDL) cholesterol (-70 to -94%) and n on-HDL cholesterol (-48 to -85%) levels in control, apoE-KO, LDLr-KO, and c holesteryl ester transfer protein-Tg mice. Transcriptome and Western blot a nalysis demonstrated up-regulation of hepatic LDLr and apoE expression in L CAT-KO mice. Despite decreased HDL, aortic atherosclerosis was significantl y reduced (-35% to -99%) in all mouse models with LCAT deficiency. Our stud ies indicate (i) that the plasma levels of apoB containing lipoproteins rat her than HDL may determine the atherogenic risk of patients with hypoalphal ipoproteinemia due to LCAT deficiency and (ii) a potential. etiological rol e for lipoproteins X in the development of glomerulosclerosis in LCAT defic iency. The availability of LCAT-KO mice characterized by lipid, hematologic , and renal abnormalities similar to familial LCAT deficiency patients will permit future evaluation of LCAT gene transfer as a possible treatment for glomerulosclerosis in LCAT-deficient states.