Lipoprotein X Causes Renal Disease in LCAT Deficiency

Abstract

Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat-/- mice, which have low HDL, but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat-/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat-/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of Lcat induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.

LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis

“…This result suggests the redistribution of the newly esterified cholesterol from Lp‐X lipids into these lipoproteins. Besides the decrease in Lp‐X, another notable change in response to the rhLCAT treatment was an overall decrease in Filipin staining for all of the other lipoproteins, which we have also previously observed and is consistent with the known ability of LCAT to esterify cholesterol.…”

“…In mice injected with rhLCAT, we observed a marked reduction of any Lp‐X band migrating below the origin for both the filipin and Sudan black stained gels (lanes 7‐9). In the Sudan‐stained gel after ANIT treatment (Figure B, bottom), the remodeling effects of rhLCAT can be seen in lanes 7‐9 by the changes in the intensity of LDL and HDL bands, as previously reported . This result suggests the redistribution of the newly esterified cholesterol from Lp‐X lipids into these lipoproteins.…”

“…In FLD, Lp‐X has clearly been shown to cause proteinuria and renal damage . Furthermore, rhLCAT treatment can prevent Lp‐X formation in animal models of FLD and prevent renal damage .…”

“…Lp‐X particles accumulate in mesangial cells of the kidney where they induce inflammation . It has been shown in mice that injection of Lp‐X can cause proteinuria and is nephrotoxic . Furthermore, recombinant LCAT can prevent Lp‐X formation and renal disease in a mouse model of LCAT deficiency .…”

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

“…The fact that LCAT deficiency in fish eye disease results in a renal lipidosis that is associated with nephrotic range proteinuria strongly suggests that the elevated ratio of plasma unesterified cholesterol:total cholesterol observed in LCAT deficiency might contribute to the development of proteinuria 71 . Lipoprotein X, an abnormal cholesterol-rich particle, might also contribute to renal disease in patients with LCAT deficiency 72 . Although more subtle than LCAT deficiency, the phenotype of patients with ABCA1 deficiency (Tangier disease) is also characterized by early atherosclerosis, very low HDL levels and mild proteinuria with foamy podocytes in kidney biopsy samples 73 .…”