December 2013

Deciphering the role of CGI-58 in lipid regulation

More than one way to trim the fat?

Comparative gene identification-58, or CGI-58, is best known as the causative gene in Chanarin-Dorfman syndrome, a rare neutral lipid-storage disease in humans that results in an abnormal accumulation of triacylglycerol, or TAG, in nonlipid-storing cell types such as muscle, heart and skin.
CGI-58, also known as alpha-beta hydrolase 5, or ABHD5, is a member of the large alpha/beta-hydrolase-fold-domain family of proteins. However, unlike many members of this family, CGI-58 itself lacks lipase activity and instead regulates TAG turnover by serving as a co-activator of major adipose triacylglycerol lipase ATGL. Yet beyond its interaction with ATGL, many of the mechanisms of CGI-58 action remain somewhat unclear, including its inherent lysophosphatidic acid acyltransferase activity (see Ghosh et al and Montero-Moran et al) and its potential role in lipid-signaling pathways.
Homologues of CGI-58 have been identified in diverse eukaryotes, including invertebrates, yeast and plants (see Ghosh et al and Ghosh et al), and in several cases there appears to be a remarkable conservation of function at the cellular level. For example, in the model plant Arabidopsis thaliana, loss of CGI-58 activity results in a Chanarin-Dorfman-like phenotype — a hyperaccumulation of TAG and lipid droplets in leaves where lipid droplets normally don’t accumulate.
However, instead of interacting with an ATGL-like lipase, Arabidopsis CGI-58 interacts with the peroxisomal ABC transporter 1 protein, also known as PXA1, which is responsible for the uptake of fatty acids into peroxisomes for β-oxidation (see Zolman et al, Footitt et al and De Marcos Lousa et al). Hence, despite the overall similarities in lipid accumulation phenotypes in plants and animals with disruptions in CGI-58, the underlying mechanisms involved in lipid regulation appear to be quite different.
Notably, PXA1 recently was shown to act as an acyl-hydrolase toward fatty acyl-CoA substrates as part of the transport cycle, suggesting that CGI-58 in plants and animals might stimulate hydrolytic activity similarly, albeit of different proteins, to promote lipid turnover ultimately. Still, because some cell types in animals use peroxisomal β-oxidation extensively for the metabolism of fatty acids and also possess ABC proteins for transport of fatty acids into peroxisomes and mitochondria and across the plasma membrane, it is possible that CGI-58 (or other related ABHD proteins) interacts with ABC transporters in a similar way to regulate other aspects of lipid metabolism and signaling in nonlipid-storing cell types of mammals (see Braverman and Moser and Morita and Imanaka).

CGI-58 and PXA1
Model depicting the interaction and cooperation of CGI-58 and PXA1 to cellular lipid homeostasis and signaling in Arabidopsis. OPDA, 12-oxo phytodienoic acid; IBA, indole butyric acid; FA, fatty acid; IAA, indole acetic acid; JA, jasmonic acid; GL, galactolipid; TAG, triacylglycerol. Figure credit: Adapted with permission from Park et al. Plant Cell 25, 1726 – 1739 (2013). Source: Copyright: American Society of Plant Biologists.

One additional and interesting aspect of CGI-58 in plant cells is that the protein is positioned at a key point in the regulation of lipid turnover and lipid signaling in plants (see figure). For instance, PXA1, in addition to playing a role in the uptake and turnover of cellular fatty acids for energy generation, also facilitates the uptake of lipophilic hormone precursors of the jasmonate and indole acetic acid pathway for their subsequent activation through β-oxidation (see Hayashi et al and Theodoulou et al 18, 19). In CGI-58 loss-of-function mutants of Arabidopsis, in addition to the increase in TAG content in leaves, the production of jasmonic acid and IAA, or auxin, are significantly impaired (see Park et al), implying that CGI-58, through its interaction with PXA1, participates in the regulation of both lipid homeostasis and hormone signaling in plants (see figure).
Hence, CGI-58 interaction with peroxisomes may be an evolutionarily ancient means for the coordination of energy supplies and regulation of growth in multicellular eukaryotes. It will be interesting to identify additional functions for CGI-58 in diverse organisms and to test such possibilities.

Kent ChapmanRobert MullenJohn DyerKent D. Chapman ( is regents professor of biochemistry and director of the Center for Plant Lipid Research at the University of North Texas in the Department of Biological Sciences in Denton, Texas. Robert T. Mullen ( is a professor, chair and university research chair at the University of Guelph’s department of molecular and cellular biology. John M. Dyer ( is a research molecular biologist and lead scientist at the U.S. Department of Agriculture-Agricultural Research Service, U.S. Arid Land Agricultural Research Center in Maricopa, Ariz.

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