Growth Retardation, Impaired Triacylglycerol Catabolism, Hepatic Steatosis, and Lethal Skin Barrier Defect in Mice Lacking Comparative Gene Identification-58 (CGI-58)

Franz P.W Radner,Ingo E Streith,Gabriele Schoiswohl,Martina Schweiger,Manju Kumari,Thomas O Eichmann,Gerald Rechberger,Harald C Koefeler,Sandra Eder,Silvia Schauer,H Christian Theussl,Karina Preiss-Landl,Achim Lass,Robert Zimmermann,Gerald Hoefler,Rudolf Zechner,Guenter Haemmerle

doi:10.1074/jbc.m109.081877

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.

Highlights

Comparative gene identification-58 (CGI-58), designated as ␣/␤-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid
Hydrolysis of TG is mediated by the enzymatic activity of adipose triglyceride lipase (ATGL) [7,8,9] and hormone-sensitive lipase [10, 11]
Mice heterozygous for the targeted allele exhibited ϳ50% reduced CGI-58 mRNA expression levels compared with wild-type mice

Summary

Introduction

Comparative gene identification-58 (CGI-58), designated as ␣/␤-hydrolase domain containing-5 (ABHD-5), is a lipid droplet-associated protein that activates adipose triglyceride lipase (ATGL) and acylates lysophosphatidic acid. CGI-58 Is Rate-limiting in MEF TG Catabolism via Activation of ATGL Enzyme Activity—To define the impact of CGI-58 deficiency on cellular TG metabolism, we isolated MEF from E12.5-day-old Cgi-58Ϫ/Ϫ, AtglϪ/Ϫ, and wild-type embryos and incubated these cells with increasing concentrations of oleic acid to induce lipogenesis. The LD-associated TG hydrolase activities of Cgi-58Ϫ/Ϫ and AtglϪ/Ϫ MEF were decreased by 76 and 81%, respectively, compared with wild-type MEF (Fig. 3B).

Results

Conclusion