CGI-58/ABHD5-derived signaling lipids regulate systemic inflammation and insulin action

Caleb C. Lord, Jenna L. Betters, Pavlina T. Ivanova, Stephen B. Milne, David S. Myers, Jennifer Madenspacher, Gwynneth Thomas, Soonkyu Chung, Mingxia Liu, Matthew A. Davis, Richard G. Lee, Rosanne M. Crooke, Mark J. Graham, John S. Parks, Dawn L. Brasaemle, Michael B. Fessler, H. Alex Brown, J. Mark Brown

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Mutations of comparative gene identification 58 (CGI-58) in humans cause Chanarin-Dorfman syndrome, a rare autosomal recessive disease in which excess triacylglycerol (TAG) accumulates in multiple tissues. CGI-58 recently has been ascribed two distinct biochemical activities, including coactivation of adipose triglyceride lipase and acylation of lysophosphatidic acid (LPA). It is noteworthy that both the substrate (LPA) and the product (phosphatidic acid) of the LPA acyltransferase reaction are wellknown signaling lipids. Therefore, we hypothesized that CGI-58 is involved in generating lipid mediators that regulate TAG metabolism and insulin sensitivity. Here, we show that CGI-58 is required for the generation of signaling lipids in response to inflammatory stimuli and that lipid second messengers generated by CGI-58 play a critical role in maintaining the balance between inflammation and insulin action. Furthermore, we show that CGI- 58 is necessary for maximal T H1 cytokine signaling in the liver. This novel role for CGI-58 in cytokine signaling may explain why diminished CGI-58 expression causes severe hepatic lipid accumulation yet paradoxically improves hepatic insulin action. Collectively, these findings establish that CGI-58 provides a novel source of signaling lipids. These findings contribute insight into the basic mechanisms linking T H1 cytokine signaling to nutrient metabolism.

Original languageEnglish (US)
Pages (from-to)355-363
Number of pages9
JournalDiabetes
Volume61
Issue number2
DOIs
StatePublished - Feb 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Lord, C. C., Betters, J. L., Ivanova, P. T., Milne, S. B., Myers, D. S., Madenspacher, J., Thomas, G., Chung, S., Liu, M., Davis, M. A., Lee, R. G., Crooke, R. M., Graham, M. J., Parks, J. S., Brasaemle, D. L., Fessler, M. B., Brown, H. A., & Brown, J. M. (2012). CGI-58/ABHD5-derived signaling lipids regulate systemic inflammation and insulin action. Diabetes, 61(2), 355-363. https://doi.org/10.2337/db11-0994