LCAT protects against Lipoprotein‐X formation in a murine model of drug‐induced intrahepatic cholestasis. Issue 1 (29th December 2019)

• Record Type: Journal Article
• Authors: 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.
• Is Part Of: Pharmacology research & perspectives. Volume 8:Issue 1(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2019-12-29
• Subjects: cholesterol acyltransferase -- cholesterol acyltransferase deficiency -- deficient mouse -- Familial lecithin -- intrahepatic cholestasis -- LCAT transgenic mouse -- lecithin -- Lipoprotein‐X; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.554
• Languages: English
• ISSNs: 2052-1707

Abstract

Abstract: 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.