title: Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58).
abstract: Comparative gene identification-58 (CGI-58), also designated as alpha/beta-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. Activation of ATGL initiates the hydrolytic catabolism of cellular triacylglycerol (TG) stores to glycerol and nonesterified fatty acids. Mutations in both ATGL and CGI-58 cause "neutral lipid storage disease" characterized by massive accumulation of TG in various tissues. The analysis of CGI-58-deficient (Cgi-58(-/-)) mice, presented in this study, reveals a dual function of CGI-58 in lipid metabolism. First, systemic TG accumulation and severe hepatic steatosis in newborn Cgi-58(-/-) mice establish a limiting role for CGI-58 in ATGL-mediated TG hydrolysis and supply of nonesterified fatty acids as energy substrate. Second, a severe skin permeability barrier defect uncovers an essential ATGL-independent role of CGI-58 in skin lipid metabolism. The neonatal lethal skin barrier defect is linked to an impaired hydrolysis of epidermal TG. As a consequence, sequestration of fatty acids in TG prevents the synthesis of acylceramides, which are essential lipid precursors for the formation of a functional skin permeability barrier. This mechanism may also underlie the pathogenesis of ichthyosis in neutral lipid storage disease patients lacking functional CGI-58.
authors.affiliation: Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
authors.forename: Franz P W
authors.initials: FP
authors.lastname: Radner
authors.forename: Ingo E
authors.initials: IE
authors.lastname: Streith
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schoiswohl
authors.forename: Martina
authors.initials: M
authors.lastname: Schweiger
authors.forename: Manju
authors.initials: M
authors.lastname: Kumari
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Eichmann
authors.forename: Gerald
authors.initials: G
authors.lastname: Rechberger
authors.forename: Harald C
authors.initials: HC
authors.lastname: Koefeler
authors.forename: Sandra
authors.initials: S
authors.lastname: Eder
authors.forename: Silvia
authors.initials: S
authors.lastname: Schauer
authors.forename: H Christian
authors.initials: HC
authors.lastname: Theussl
authors.forename: Karina
authors.initials: K
authors.lastname: Preiss-Landl
authors.forename: Achim
authors.initials: A
authors.lastname: Lass
authors.forename: Robert
authors.initials: R
authors.lastname: Zimmermann
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Guenter
authors.initials: G
authors.lastname: Haemmerle
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D000833:Animals, Suckling / Q000502:physiology; D002265:Carboxylic Ester Hydrolases / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism*; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006801:Humans; D007057:Ichthyosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010539:Permeability; D012867:Skin / Q000737:chemistry / Q000473:pathology / Q000503:physiopathology; D013577:Syndrome; D014280:Triglycerides / Q000378:metabolism*; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D002265:Carboxylic Ester Hydrolases; D008049:Lipase; D014280:Triglycerides; C439972:ABHD5 protein, human; C492986:Abhd5 protein, mouse; C494794:PNPLA2 protein, human; D000217:Acyltransferases; C494445:PNPLA2 protein, mouse