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Originally published In Press as doi:10.1194/jlr.M700279-JLR200 on July 30, 2007

Papers In Press, published online ahead of print October 1, 2007
J. Lipid Res., doi:10.1194/jlr.M700279-JLR200
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Journal of Lipid Research, Vol. 48, 2295-2305, October 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cellsboxs

J. Mark Brown*, Soonkyu Chung*, Akash Das{dagger}, Gregory S. Shelness*, Lawrence L. Rudel*,{dagger} and Liqing Yu1,*

* Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040
{dagger} Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040

boxs The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of 2 figures.

Published, JLR Papers in Press, July 30, 2007.

1 To whom correspondence should be addressed. e-mail: lyu{at}wfubmc.edu

Comparative Gene Identification-58 (CGI-58) is a member of the {alpha}/ß-hydrolase family of proteins. Mutations in the human CGI-58 gene are associated with Chanarin-Dorfman syndrome, a rare autosomal recessive genetic disease in which excessive triglyceride (TG) accumulation occurs in multiple tissues. In this study, we investigated the role of CGI-58 in cellular lipid metabolism in several cell models and discovered a role for CGI-58 in promoting the packaging of cytoplasmic TG into secreted lipoprotein particles in hepatoma cells. Using both gain-of-function and loss-of-function approaches, we demonstrate that CGI-58 facilitates the depletion of cellular TG stores without altering cellular cholesterol or phospholipid accumulation. This depletion of cellular TG is attributable solely to augmented hydrolysis, whereas TG synthesis was not affected by CGI-58. Furthermore, CGI-58-mediated TG hydrolysis can be completely inhibited by the known lipase inhibitors diethylumbelliferyl phosphate and diethyl-p-nitrophenyl phosphate, but not by p-chloro-mercuribenzoate. Intriguingly, CGI-58-driven TG hydrolysis was coupled to increases in both fatty acid oxidation and secretion of TG. Collectively, this study reveals a role for CGI-58 in coupling lipolytic degradation of cytoplasmic TG to oxidation and packaging into TG-rich lipoproteins for secretion in hepatoma cells.

Supplementary key words Comparative Gene Identification-58 • triglyceride hydrolysis • lipolysis

Abbreviations: ADRP, adipose differentiation-related protein; apoB, apolipoprotein B; ATGL, adipose triglyceride lipase; CDS, Chanarin-Dorfman syndrome; CE, cholesteryl ester; CGI-58, Comparative Gene Identification-58; DEUP, diethylumbelliferyl phosphate; E-600, diethyl-p-nitrophenyl phosphate; EGFP, enhanced green fluorescent protein; ER, endoplasmic reticulum; IDL, intermediate density lipoprotein; iPLA2{zeta}, calcium-independent phospholipase A2{zeta}; LD, lipid droplet; MTP, microsomal triglyceride transfer protein; PCMB, p-chloro-mercuribenzoate; PL, phospholipid; siRNA, short interfering RNA; TG, triglyceride


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A. K. Ghosh, G. Ramakrishnan, C. Chandramohan, and R. Rajasekharan
CGI-58, the Causative Gene for Chanarin-Dorfman Syndrome, Mediates Acylation of Lysophosphatidic Acid
J. Biol. Chem., September 5, 2008; 283(36): 24525 - 24533.
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