LCAT enzyme replacement therapy reduces LpX and improves kidney function in a mouse model of familial LCAT deficiency

Boris L. Vaisman, Edward B. Neufeld, Lita A. Freeman, Scott M. Gordon, Maureen L. Sampson, Milton Pryor, Emily Hillman, Milton J. Axley, Sotirios K. Karathanasis, Alan T. Remaley

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Familial LCAT deficiency (FLD) is due to mutations in lecithin: cholesterol acyltransferase (LCAT), a plasma enzyme that esterifies cholesterol on lipoproteins. FLD is associated with markedly reduced levels of plasma high-density lipoprotein and cholesteryl ester and the formation of a nephrotoxic lipoprotein called LpX. We used a mouse model in which the LCAT gene is deleted and a truncated version of the SREBP1a gene is expressed in the liver under the control of a protein-rich/carbohydrate-low (PRCL) diet-regulated PEPCK promoter. This mouse was found to form abundant amounts of LpX in the plasma and was used to determine whether treatment with recombinant human LCAT (rhLCAT) could prevent LpX formation and renal injury. After 9 days on the PRCL diet, plasma total and free cholesterol, as well as phospholipids, increased 6.1 6 0.6-, 9.6 6 0.9-, and 6.7 6 0.7-fold, respectively, and liver cholesterol and triglyceride concentrations increased 1.7 6 0.4- and 2.8 6 0.9-fold, respectively, compared with chow-fed animals. Transmission electron microscopy revealed robust accumulation of lipid droplets in hepatocytes and the appearance of multilamellar LpX particles in liver sinusoids and bile canaliculi. In the kidney, LpX was found in glomerular endothelial cells, podocytes, the glomerular basement membrane, and the mesangium. The urine albumin/creatinine ratio increased 30-fold on the PRCL diet compared with chow-fed controls. Treatment of these mice with intravenous rhLCAT restored the normal lipoprotein profile, eliminated LpX in plasma and kidneys, and markedly decreased proteinuria. The combined results suggest that rhLCAT infusion could be an effective therapy for the prevention of renal disease in patients with FLD.

Original languageEnglish
Pages (from-to)423
Number of pages1
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Mar 1 2019

Bibliographical note

Publisher Copyright:
© 2019 American Society for Pharmacology and Experimental Therapy. All rights reserved.

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


Dive into the research topics of 'LCAT enzyme replacement therapy reduces LpX and improves kidney function in a mouse model of familial LCAT deficiency'. Together they form a unique fingerprint.

Cite this