title: Hepatic cholesteryl ester accumulation in lysosomal acid lipase deficiency: non-invasive identification and treatment monitoring by magnetic resonance.
abstract: OBJECTIVE
  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 (1)H 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 4weeks of sebelipase alfa treatment. Hepatic (1)H 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.
authors.affiliation: Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK. pete.thelwall@newcastle.ac.uk
authors.forename: Peter E
authors.initials: PE
authors.lastname: Thelwall
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Smith
authors.forename: Mark C
authors.initials: MC
authors.lastname: Leavitt
authors.forename: David
authors.initials: D
authors.lastname: Canty
authors.forename: Wei
authors.initials: W
authors.lastname: Hu
authors.forename: Kieren G
authors.initials: KG
authors.lastname: Hollingsworth
authors.forename: Christian
authors.initials: C
authors.lastname: Thoma
authors.forename: Michael I
authors.initials: MI
authors.lastname: Trenell
authors.forename: Roy
authors.initials: R
authors.lastname: Taylor
authors.forename: Joseph V
authors.initials: JV
authors.lastname: Rutkowski
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blamire
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Quinn
mesh_terms: D000818:Animals; D002788:Cholesterol Esters / Q000378:metabolism*; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease; D011446:Prospective Studies; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D011994:Recombinant Proteins / Q000627:therapeutic use; D002787:Sterol Esterase / Q000172:deficiency* / Q000235:genetics / Q000627:therapeutic use; D014280:Triglycerides / Q000378:metabolism; D015223:Wolman Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D005227:Fatty Acids; D011994:Recombinant Proteins; D014280:Triglycerides; C503451:LIPA protein, human; D002787:Sterol Esterase
keywords: (1)H MR spectroscopy; (13)C MR spectroscopy; CE; CESD; Cholesteryl ester storage disease; ERT; Enzyme replacement therapy; LAL; LAL deficiency; LIPA; Liver fat; Lysosomal acid lipase; NAFLD; Sebelipase alfa; TG; Wolman disease; cholesteryl ester; cholesteryl ester storage disease; enzyme replacement therapy; lysosomal acid lipase; non-alcoholic fatty liver disease; triglyceride