CGI-58/ABHD5-Derived Signaling Lipids Regulate Systemic Inflammation and Insulin Action

Authors

Caleb C. Lord, Wake Forest University School of Medicine
Jenna L. Betters, Wake Forest University School of Medicine
Pavlina T. Ivanova, Vanderbilt University School of Medicine
Stephen B. Milne, Vanderbilt University School of Medicine
David S. Myers, Vanderbilt University School of Medicine
Jennifer Madenspacher, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
Gwynneth Thomas, Wake Forest University School of Medicine
Soonkyu Chung, University of Nebraska-LincolnFollow
Mingxia Liu, Wake Forest University School of Medicine
Matthew A. Davis, Wake Forest University School of Medicine
Richard G. Lee, Isis Pharmaceuticals, Carlsbad, California
Rosanne M. Crooke, Isis Pharmaceuticals, Carlsbad, California
Mark J. Graham, Isis Pharmaceuticals, Carlsbad, California
John S. Parks, Wake Forest University School of MedicineFollow
Dawn L. Brasaemle, The State University of New Jersey, New Brunswick, New Jersey
Michael B. Fessler, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina
H. Alex Brown, Vanderbilt University School of Medicine
J. Mark Brown, Wake Forest University School of Medicine

Date of this Version

2012

Citation

Diabetes 61:355–363, 2012

Comments

Open Access licensed.

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.