LCAT Enzyme Replacement Therapy Reduces LpX and Improves Kidney Function in a Mouse Model of Familial LCAT Deficiency

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

doi:10.1124/jpet.118.251876

Cited by 26 publications

(23 citation statements)

References 45 publications

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“…A major finding from this study is that LCAT can prevent the formation of Lp‐X from cholestasis. We have previously shown that rhLCAT can promote both in vitro and in vivo dissolution of Lp‐X formed due to LCAT deficiency . In the case of Lp‐X formed in LCAT deficiency, it has been shown that esterification of cholesterol by adding exogenous LCAT causes the Lp‐X particles to spontaneously remodel and when Lp‐X is treated with LCAT in the presence of apoA‐I, HDL‐like particles can be formed .…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that rhL-CAT can promote both in vitro and in vivo dissolution of Lp-X formed due to LCAT deficiency. 5,19,20 In the case of Lp-X formed in LCAT deficiency, it has been shown that esterification of cholesterol by adding exogenous LCAT causes the Lp-X particles to spontaneously remodel and when Lp-X is treated with LCAT in the presence of apoA-I, HDL-like particles can be formed. 20 This suggests that the stability of Lp-X is largely due to the physiochemical properties of its lipid components, free cholesterol and phospholipid.…”

Section: Discussionmentioning

confidence: 99%

“…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 . Because LCAT has a half‐life of several days, a recombinant form of LCAT has been developed as a potential enzyme replacement therapy for FLD .…”

Section: Introductionmentioning

confidence: 99%

“…18 Furthermore, recombinant LCAT can prevent Lp-X formation and renal disease in a mouse model of LCAT deficiency. 19 Because LCAT has a half-life of several days, a recombinant form of LCAT has been developed as a potential enzyme replacement therapy for FLD. [20][21][22] FLD patients, however, do not typically develop cholestasis so the mechanism for formation of Lp-X in this disorder is thought to be different than in cholestatic liver disease.…”

Section: Introductionmentioning

confidence: 99%

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

Amar

Freeman

Nishida

et al. 2019

Pharmacology Res & Perspec

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Amar

Freeman

Nishida

et al. 2019

Pharmacology Res & Perspec

Self Cite

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“…The main symptoms of FLD patients are renal failure and corneal opacities. LpX accumulation in tissue appears to be the main cause of kidney injury ( 4 , 7 ). Similar LpX accumulation in the cornea may also contribute to corneal opacities and impaired vision in these patients.…”

Section: The Discoveries Of Lcat and Fld: Two Serendipities (K R Nomentioning

confidence: 99%

Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings

Norum

Remaley

Miettinen

et al. 2020

Journal of Lipid Research

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Lecithin:cholesterol acyltransferase (LCAT) converts free cholesterol to cholesteryl esters in the process of reverse cholesterol transport. Familial LCAT deficiency (FLD) is a genetic disease that was first described by Kaare R. Norum and Egil Gjone in 1967. This report is a summary from a 2017 symposium where Dr. Norum recounted the history of FLD and leading experts on LCAT shared their results. The Tesmer lab shared structural findings on LCAT and the close homolog lysosomal phospholipase A2. Results from studies of FLD patients in Finland, Brazil, Norway, and Italy were presented, as well as the status of a patient registry. Drs. Kuivenhoven and Calabresi presented data from carriers of genetic mutations suggesting that FLD does not necessarily accelerate atherosclerosis. Dr. Ng shared that LCAT null mice were protected from diet-induced obesity, insulin resistance and non-alcoholic fatty liver disease. Dr. Zhou presented multiple innovations for increasing LCAT activity for therapeutic purposes, whereas Dr. Remaley showed results from treatment of an FLD patient with rhLCAT. Dr. Karathanasis showed that rhLCAT infusion in mice stimulates cholesterol efflux and suggested that it could also enhance cholesterol efflux from macrophages. While the role of LCAT in atherosclerosis remains elusive, the consensus is that a continued study of both the enzyme and disease will lead towards better treatments for patients with heart disease and FLD.

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High Density Lipoproteins: Is There a Comeback as a Therapeutic Target?

Eckardstein

2021

Handbook of Experimental Pharmacology

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Low plasma levels of High Density Lipoprotein (HDL) cholesterol (HDL-C) are associated with increased risks of atherosclerotic cardiovascular disease (ASCVD). In cell culture and animal models, HDL particles exert multiple potentially anti-atherogenic effects. However, drugs increasing HDL-C have failed to prevent cardiovascular endpoints. Mendelian Randomization studies neither found any genetic causality for the associations of HDL-C levels with differences in cardiovascular risk. Therefore, the causal role and, hence, utility as a therapeutic target of HDL has been questioned. However, the biomarker “HDL-C” as well as the interpretation of previous data has several important limitations: First, the inverse relationship of HDL-C with risk of ASCVD is neither linear nor continuous. Hence, neither the-higher-the-better strategies of previous drug developments nor previous linear cause-effect relationships assuming Mendelian randomization approaches appear appropriate. Second, most of the drugs previously tested do not target HDL metabolism specifically so that the futile trials question the clinical utility of the investigated drugs rather than the causal role of HDL in ASCVD. Third, the cholesterol of HDL measured as HDL-C neither exerts nor reports any HDL function. Comprehensive knowledge of structure-function-disease relationships of HDL particles and associated molecules will be a pre-requisite, to test them for their physiological and pathogenic relevance and exploit them for the diagnostic and therapeutic management of individuals at HDL-associated risk of ASCVD but also other diseases, for example diabetes, chronic kidney disease, infections, autoimmune and neurodegenerative diseases.

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LCAT Enzyme Replacement Therapy Reduces LpX and Improves Kidney Function in a Mouse Model of Familial LCAT Deficiency

Cited by 26 publications

References 45 publications

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

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

Lecithin:cholesterol acyltransferase: symposium on 50 years of biomedical research from its discovery to latest findings

High Density Lipoproteins: Is There a Comeback as a Therapeutic Target?

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