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

J. Mark Brown, Soonkyu Chung, Akash Das, Gregory S. Shelness, Lawrence L. Rudel, Liqing Yu

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Comparative Gene Identification-58 (CGI-58) is a member of the α/β-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.

Original languageEnglish (US)
Pages (from-to)2295-2305
Number of pages11
JournalJournal of Lipid Research
Volume48
Issue number10
DOIs
StatePublished - Oct 1 2007

Fingerprint

Lipoproteins
Hepatocellular Carcinoma
Triglycerides
Genes
Hydrolysis
Product Packaging
Packaging
Mercuribenzoates
Paraoxon
Oxidation
Inborn Genetic Diseases
Hydrolases
Lipase
Lipid Metabolism
Phospholipids
Fatty Acids
Cholesterol
Tissue
Degradation
Mutation

Keywords

  • Comparative Gene Identification-58
  • Lipolysis
  • Triglyceride hydrolysis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells. / Brown, J. Mark; Chung, Soonkyu; Das, Akash; Shelness, Gregory S.; Rudel, Lawrence L.; Yu, Liqing.

In: Journal of Lipid Research, Vol. 48, No. 10, 01.10.2007, p. 2295-2305.

Research output: Contribution to journalArticle

Brown, J. Mark ; Chung, Soonkyu ; Das, Akash ; Shelness, Gregory S. ; Rudel, Lawrence L. ; Yu, Liqing. / CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells. In: Journal of Lipid Research. 2007 ; Vol. 48, No. 10. pp. 2295-2305.
@article{f2c0e58923af44a1a9de00135b46c540,
title = "CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells",
abstract = "Comparative Gene Identification-58 (CGI-58) is a member of the α/β-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.",
keywords = "Comparative Gene Identification-58, Lipolysis, Triglyceride hydrolysis",
author = "Brown, {J. Mark} and Soonkyu Chung and Akash Das and Shelness, {Gregory S.} and Rudel, {Lawrence L.} and Liqing Yu",
year = "2007",
month = "10",
day = "1",
doi = "10.1194/jlr.M700279-JLR200",
language = "English (US)",
volume = "48",
pages = "2295--2305",
journal = "Journal of Lipid Research",
issn = "0022-2275",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "10",

}

TY - JOUR

T1 - CGI-58 facilitates the mobilization of cytoplasmic triglyceride for lipoprotein secretion in hepatoma cells

AU - Brown, J. Mark

AU - Chung, Soonkyu

AU - Das, Akash

AU - Shelness, Gregory S.

AU - Rudel, Lawrence L.

AU - Yu, Liqing

PY - 2007/10/1

Y1 - 2007/10/1

N2 - Comparative Gene Identification-58 (CGI-58) is a member of the α/β-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.

AB - Comparative Gene Identification-58 (CGI-58) is a member of the α/β-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.

KW - Comparative Gene Identification-58

KW - Lipolysis

KW - Triglyceride hydrolysis

UR - http://www.scopus.com/inward/record.url?scp=34948871632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34948871632&partnerID=8YFLogxK

U2 - 10.1194/jlr.M700279-JLR200

DO - 10.1194/jlr.M700279-JLR200

M3 - Article

VL - 48

SP - 2295

EP - 2305

JO - Journal of Lipid Research

JF - Journal of Lipid Research

SN - 0022-2275

IS - 10

ER -