Lipoprotein X causes renal disease in LCAT deficiency

Alice Ossoli, Edward B. Neufeld, Seth G. Thacker, Boris Vaisman, Milton Pryor, Lita A. Freeman, Christine A. Brantner, Irina Baranova, Nicolás O. Francone, Stephen J. Demosky, Cecilia Vitali, Monica Locatelli, Mauro Abbate, Carlamaria Zoja, Guido Franceschini, Laura Calabresi, Alan T. Remaley

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)e0150083
JournalPLoS One
Volume11
Issue number2
DOIs
Publication statusPublished - Feb 1 2016

Fingerprint

Lipoprotein-X
Lecithin Cholesterol Acyltransferase Deficiency
phosphatidylcholine-choline acyltransferase
Phosphatidylcholine-Sterol O-Acyltransferase
kidney diseases
lipoproteins
Kidney
Podocytes
mice
Mesangial Cells
kidneys
Plasmas
nephrosis
Nephrosis
Apolipoprotein A-I
Endothelial cells
lysosomes
Biomarkers

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Ossoli, A., Neufeld, E. B., Thacker, S. G., Vaisman, B., Pryor, M., Freeman, L. A., ... Remaley, A. T. (2016). Lipoprotein X causes renal disease in LCAT deficiency. PLoS One, 11(2), e0150083. https://doi.org/10.1371/journal.pone.0150083

Lipoprotein X causes renal disease in LCAT deficiency. / Ossoli, Alice; Neufeld, Edward B.; Thacker, Seth G.; Vaisman, Boris; Pryor, Milton; Freeman, Lita A.; Brantner, Christine A.; Baranova, Irina; Francone, Nicolás O.; Demosky, Stephen J.; Vitali, Cecilia; Locatelli, Monica; Abbate, Mauro; Zoja, Carlamaria; Franceschini, Guido; Calabresi, Laura; Remaley, Alan T.

In: PLoS One, Vol. 11, No. 2, 01.02.2016, p. e0150083.

Research output: Contribution to journalArticle

Ossoli, A, Neufeld, EB, Thacker, SG, Vaisman, B, Pryor, M, Freeman, LA, Brantner, CA, Baranova, I, Francone, NO, Demosky, SJ, Vitali, C, Locatelli, M, Abbate, M, Zoja, C, Franceschini, G, Calabresi, L & Remaley, AT 2016, 'Lipoprotein X causes renal disease in LCAT deficiency', PLoS One, vol. 11, no. 2, pp. e0150083. https://doi.org/10.1371/journal.pone.0150083
Ossoli A, Neufeld EB, Thacker SG, Vaisman B, Pryor M, Freeman LA et al. Lipoprotein X causes renal disease in LCAT deficiency. PLoS One. 2016 Feb 1;11(2):e0150083. https://doi.org/10.1371/journal.pone.0150083
Ossoli, Alice ; Neufeld, Edward B. ; Thacker, Seth G. ; Vaisman, Boris ; Pryor, Milton ; Freeman, Lita A. ; Brantner, Christine A. ; Baranova, Irina ; Francone, Nicolás O. ; Demosky, Stephen J. ; Vitali, Cecilia ; Locatelli, Monica ; Abbate, Mauro ; Zoja, Carlamaria ; Franceschini, Guido ; Calabresi, Laura ; Remaley, Alan T. / Lipoprotein X causes renal disease in LCAT deficiency. In: PLoS One. 2016 ; Vol. 11, No. 2. pp. e0150083.
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