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

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL‐C levels, low plasma cholesterol esterification, and the formation of Lipoprotein‐X (Lp‐X), an abnormal cholesterol‐rich lipoprotein particle. LCAT deficiency causes corneal opaci...

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Autores principales: Amar, Marcelo J. A., Freeman, Lita A., Nishida, Takafumi, Sampson, Maureen L., Pryor, Milton, Vaisman, Boris L., Neufeld, Edward B., Karathanasis, Sotirios K., Remaley, Alan T.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935572/
https://www.ncbi.nlm.nih.gov/pubmed/31893124
http://dx.doi.org/10.1002/prp2.554
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author Amar, Marcelo J. A.
Freeman, Lita A.
Nishida, Takafumi
Sampson, Maureen L.
Pryor, Milton
Vaisman, Boris L.
Neufeld, Edward B.
Karathanasis, Sotirios K.
Remaley, Alan T.
author_facet Amar, Marcelo J. A.
Freeman, Lita A.
Nishida, Takafumi
Sampson, Maureen L.
Pryor, Milton
Vaisman, Boris L.
Neufeld, Edward B.
Karathanasis, Sotirios K.
Remaley, Alan T.
author_sort Amar, Marcelo J. A.
collection PubMed
description Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL‐C levels, low plasma cholesterol esterification, and the formation of Lipoprotein‐X (Lp‐X), an abnormal cholesterol‐rich lipoprotein particle. LCAT deficiency causes corneal opacities, normochromic normocytic anemia, and progressive renal disease due to Lp‐X deposition in the glomeruli. Recombinant LCAT is being investigated as a potential therapy for this disorder. Several hepatic disorders, namely primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and chronic alcoholism also develop Lp‐X, which may contribute to the complications of these disorders. We aimed to test the hypothesis that an increase in plasma LCAT could prevent the formation of Lp‐X in other diseases besides FLD. We generated a murine model of intrahepatic cholestasis in LCAT‐deficient (KO), wild type (WT), and LCAT‐transgenic (Tg) mice by gavaging mice with alpha‐naphthylisothiocyanate (ANIT), a drug well known to induce intrahepatic cholestasis. Three days after the treatment, all mice developed hyperbilirubinemia and elevated liver function markers (ALT, AST, Alkaline Phosphatase). The presence of high levels of LCAT in the LCAT‐Tg mice, however, prevented the formation of Lp‐X and other plasma lipid abnormalities in WT and LCAT‐KO mice. In addition, we demonstrated that multiple injections of recombinant human LCAT can prevent significant accumulation of Lp‐X after ANIT treatment in WT mice. In summary, LCAT can protect against the formation of Lp‐X in a murine model of cholestasis and thus recombinant LCAT could be a potential therapy to prevent the formation of Lp‐X in other diseases besides FLD.
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spelling pubmed-69355722019-12-31 LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis Amar, Marcelo J. A. Freeman, Lita A. Nishida, Takafumi Sampson, Maureen L. Pryor, Milton Vaisman, Boris L. Neufeld, Edward B. Karathanasis, Sotirios K. Remaley, Alan T. Pharmacol Res Perspect Original Articles Familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is a rare genetic disease characterized by low HDL‐C levels, low plasma cholesterol esterification, and the formation of Lipoprotein‐X (Lp‐X), an abnormal cholesterol‐rich lipoprotein particle. LCAT deficiency causes corneal opacities, normochromic normocytic anemia, and progressive renal disease due to Lp‐X deposition in the glomeruli. Recombinant LCAT is being investigated as a potential therapy for this disorder. Several hepatic disorders, namely primary biliary cirrhosis, primary sclerosing cholangitis, cholestatic liver disease, and chronic alcoholism also develop Lp‐X, which may contribute to the complications of these disorders. We aimed to test the hypothesis that an increase in plasma LCAT could prevent the formation of Lp‐X in other diseases besides FLD. We generated a murine model of intrahepatic cholestasis in LCAT‐deficient (KO), wild type (WT), and LCAT‐transgenic (Tg) mice by gavaging mice with alpha‐naphthylisothiocyanate (ANIT), a drug well known to induce intrahepatic cholestasis. Three days after the treatment, all mice developed hyperbilirubinemia and elevated liver function markers (ALT, AST, Alkaline Phosphatase). The presence of high levels of LCAT in the LCAT‐Tg mice, however, prevented the formation of Lp‐X and other plasma lipid abnormalities in WT and LCAT‐KO mice. In addition, we demonstrated that multiple injections of recombinant human LCAT can prevent significant accumulation of Lp‐X after ANIT treatment in WT mice. In summary, LCAT can protect against the formation of Lp‐X in a murine model of cholestasis and thus recombinant LCAT could be a potential therapy to prevent the formation of Lp‐X in other diseases besides FLD. John Wiley and Sons Inc. 2019-12-29 /pmc/articles/PMC6935572/ /pubmed/31893124 http://dx.doi.org/10.1002/prp2.554 Text en © 2019 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Original Articles
Amar, Marcelo J. A.
Freeman, Lita A.
Nishida, Takafumi
Sampson, Maureen L.
Pryor, Milton
Vaisman, Boris L.
Neufeld, Edward B.
Karathanasis, Sotirios K.
Remaley, Alan T.
LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis
title LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis
title_full LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis
title_fullStr LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis
title_full_unstemmed LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis
title_short LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis
title_sort lcat protects against lipoprotein‐x formation in a murine model of drug‐induced intrahepatic cholestasis
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935572/
https://www.ncbi.nlm.nih.gov/pubmed/31893124
http://dx.doi.org/10.1002/prp2.554
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