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Lookup NU author(s): Professor Peter Thelwall, Dr Fiona Smith, Dr Christian Thoma, Professor Mike TrenellORCiD, Professor Roy Taylor, Professor Andrew BlamireORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Background & Aims: Lysosomal Acid Lipase (LAL) deficiency is a rare metabolic storage disease, caused by a marked reduction in activity of LAL, which leads to accumulation of cholesteryl esters (CE) and triglycerides (TG) in lysosomes in many tissues. We used 1H magnetic resonance (MR) spectroscopy to characterize the abnormalities in hepatic lipid content and composition in patients with LAL deficiency, and in ex vivo liver tissue from a LAL deficiency rat model. Secondly, we used MR spectroscopy to monitor the effects of an enzyme replacement therapy (ERT), sebelipase alfa (a recombinant human lysosomal acid lipase), on hepatic TG and CE content in the preclinical model. Methods: Human studies employed cohorts of LAL-deficient patients and NAFLD subjects. Rat experimental groups comprised ex vivo liver samples of wild type, NAFLD, LAL-deficient, and LAL-deficient rats receiving 4 weeks of sebelipase alfa treatment. Hepatic 1H MR spectroscopy was performed using 3T (human) and 7T (preclinical) MRI scanners to quantify hepatic cholesterol and triglyceride content. Results: CE accumulation was identified in LAL deficiency in both human and preclinical studies. A significant decrease in hepatic CE was observed in LAL-deficient rats following treatment with sebelipase alfa. Conclusions: We demonstrate an entirely non-invasive method to identify and quantify the hepatic lipid signature associated with a rare genetic cause of fatty liver. The approach provides a more favorable alternative to repeated biopsy sampling for diagnosis and disease progression / treatment monitoring of patients with LAL deficiency and other disorders characterised by increased free cholesterol and/or cholesteryl esters.
Author(s): Thelwall PE, Smith FE, Leavitt MC, Canty D, Hu W, Hollingsworth KG, Thoma C, Trenell MI, Taylor R, Rutkowski JV, Blamire AM, Quinn AG
Publication type: Article
Publication status: Published
Journal: Journal of Hepatology
Year: 2013
Volume: 59
Issue: 3
Pages: 543-549
Print publication date: 01/09/2013
Online publication date: 25/04/2013
Acceptance date: 16/04/2013
Date deposited: 10/01/2014
ISSN (print): 0168-8278
ISSN (electronic): 1600-0641
Publisher: Elsevier
URL: http://dx.doi.org/10.1016/j.jhep.2013.04.016
DOI: 10.1016/j.jhep.2013.04.016
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