Growth retardation, impaired triacylglycerol catabolism, hepatic steatosis, and lethal skin barrier defect in mice lacking comparative gene identification-58 (CGI-58).
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.
Radner
Franz P W
FP
Institute of Molecular Biosciences, University of Graz, Heinrichstrasse 31, A-8010 Graz, Austria.
Streith
Ingo E
IE
Schoiswohl
Gabriele
G
Schweiger
Martina
M
Kumari
Manju
M
Eichmann
Thomas O
TO
Rechberger
Gerald
G
Koefeler
Harald C
HC
Eder
Sandra
S
Schauer
Silvia
S
Theussl
H Christian
HC
Preiss-Landl
Karina
K
Lass
Achim
A
Zimmermann
Robert
R
Hoefler
Gerald
G
Zechner
Rudolf
R
Haemmerle
Guenter
G
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
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