title: Lysosomal Acid Lipase Hydrolyzes Retinyl Ester and Affects Retinoid Turnover.
abstract: Lysosomal acid lipase (LAL) is essential for the clearance of endocytosed cholesteryl ester and triglyceride-rich chylomicron remnants. Humans and mice with defective or absent LAL activity accumulate large amounts of cholesteryl esters and triglycerides in multiple tissues. Although chylomicrons also contain retinyl esters (REs), a role of LAL in the clearance of endocytosed REs has not been reported. In this study, we found that murine LAL exhibits RE hydrolase activity. Pharmacological inhibition of LAL in the human hepatocyte cell line HepG2, incubated with chylomicrons, led to increased accumulation of REs in endosomal/lysosomal fractions. Furthermore, pharmacological inhibition or genetic ablation of LAL in murine liver largely reduced in vitro acid RE hydrolase activity. Interestingly, LAL-deficient mice exhibited increased RE content in the duodenum and jejunum but decreased RE content in the liver. Furthermore, LAL-deficient mice challenged with RE gavage exhibited largely reduced post-prandial circulating RE content, indicating that LAL is required for efficient nutritional vitamin A availability. In summary, our results indicate that LAL is the major acid RE hydrolase and required for functional retinoid homeostasis.
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Lukas
authors.initials: L
authors.lastname: Grumet
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Ulrike
authors.identifier: 0000-0001-9000-1602
authors.initials: U
authors.lastname: Taschler
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Kathrin A
authors.initials: KA
authors.lastname: Zierler
authors.affiliation: the Institute of Molecular Biology and Biochemistry and.
authors.forename: Christina
authors.initials: C
authors.lastname: Leopold
authors.affiliation: Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Tarek
authors.initials: T
authors.lastname: Moustafa
authors.affiliation: the Institute of Molecular Biology and Biochemistry and.
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Romauch
authors.affiliation: the Department of Pathology and Laboratory Medicine and Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Cong
authors.initials: C
authors.lastname: Yan
authors.affiliation: the Department of Pathology and Laboratory Medicine and Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, and.
authors.forename: Hong
authors.identifier: 0000-0001-6652-4702
authors.initials: H
authors.lastname: Du
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.affiliation: Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.affiliation: the Institute of Molecular Biology and Biochemistry and.
authors.forename: Dagmar
authors.identifier: 0000-0003-1357-7573
authors.initials: D
authors.lastname: Kratky
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
authors.forename: Robert
authors.identifier: 0000-0002-7354-870X
authors.initials: R
authors.lastname: Zimmermann
authors.affiliation: From the Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria, BioTechMed, Graz 8010, Austria achim.lass@uni-graz.at.
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
mesh_terms: D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism*; D002788:Cholesterol Esters / Q000235:genetics / Q000378:metabolism; D053298:Chylomicron Remnants / Q000235:genetics / Q000378:metabolism; D004386:Duodenum / Q000201:enzymology*; D006801:Humans; D007583:Jejunum / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D012176:Retinoids / Q000235:genetics / Q000378:metabolism*; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D053298:Chylomicron Remnants; D012176:Retinoids; D014280:Triglycerides; D002265:Carboxylic Ester Hydrolases; C022523:retinyl esterase; D002787:Sterol Esterase; C505054:lysosomal acid lipase, mouse
keywords: hydrolase; knockout mouse; lipase; lysosomal acid lipase; retinoid; retinol; retinyl ester; vitamin A