The lipase cofactor CGI58 controls placental lipolysis
Jennifer Guerrero-Santoro, Mayumi Morizane, Soo-Young Oh, Takuya Mishima, Julie P. Goff, Ibrahim Bildirici, Elena Sadovsky, Yingshi Ouyang, Vladimir A. Tyurin, Yulia Y. Tyurina, Valerian E. Kagan, Yoel Sadovsky
Jennifer Guerrero-Santoro, Mayumi Morizane, Soo-Young Oh, Takuya Mishima, Julie P. Goff, Ibrahim Bildirici, Elena Sadovsky, Yingshi Ouyang, Vladimir A. Tyurin, Yulia Y. Tyurina, Valerian E. Kagan, Yoel Sadovsky
View: Text | PDF
Research Article Reproductive biology

The lipase cofactor CGI58 controls placental lipolysis

Abstract

In eutherians, the placenta plays a critical role in the uptake, storage, and metabolism of lipids. These processes govern the availability of fatty acids to the developing fetus, where inadequate supply has been associated with substandard fetal growth. Whereas lipid droplets are essential for the storage of neutral lipids in the placenta and many other tissues, the processes that regulate placental lipid droplet lipolysis remain largely unknown. To assess the role of triglyceride lipases and their cofactors in determining placental lipid droplet and lipid accumulation, we assessed the role of patatin like phospholipase domain containing 2 (PNPLA2) and comparative gene identification-58 (CGI58) in lipid droplet dynamics in the human and mouse placenta. While both proteins are expressed in the placenta, the absence of CGI58, not PNPLA2, markedly increased placental lipid and lipid droplet accumulation. These changes were reversed upon restoration of CGI58 levels selectively in the CGI58-deficient mouse placenta. Using co-immunoprecipitation, we found that, in addition to PNPLA2, PNPLA9 interacts with CGI58. PNPLA9 was dispensable for lipolysis in the mouse placenta yet contributed to lipolysis in human placental trophoblasts. Our findings establish a crucial role for CGI58 in placental lipid droplet dynamics and, by extension, in nutrient supply to the developing fetus.

Authors

Jennifer Guerrero-Santoro, Mayumi Morizane, Soo-Young Oh, Takuya Mishima, Julie P. Goff, Ibrahim Bildirici, Elena Sadovsky, Yingshi Ouyang, Vladimir A. Tyurin, Yulia Y. Tyurina, Valerian E. Kagan, Yoel Sadovsky

×

Figure 3

CGI58 interacts with PNPLA9 in the placenta.

Options: View larger image (or click on image) Download as PowerPoint
CGI58 interacts with PNPLA9 in the placenta. (A) CGI58 cross-linked with...
(A) CGI58 cross-linked with Sulfo-SBED interacts with endogenous Pnpla9 in mouse placenta. Purified BSA and His-CGI58 were UV–cross-linked with Sulfo-SBED and mixed with WT mouse placental lysate, then pulled down using streptavidin beads as detailed in Methods and processed for Western blot (WB) for CGI58 and PNPLA9. Note that CGI58 was conjugated to Sulfo-SBED in the third lane and, hence, shows a higher band. (B) Purified His-CGI58 interacts with endogenous PNPLA9 in a mouse placenta lysate. The immunoprecipitations were performed overnight with either IgG (control) or anti-His antibody and processed for His-CGI58 or PNPLA9 blots, as detailed in Methods. (C) Overexpressed His-CGI58 interacts with overexpressed FLAG-PNPLA9 in HEK293T cells. Transfections, overnight immunoprecipitation (IP), and blotting were performed as detailed in Methods. WB was performed using anti-FLAG antibody. (D) Overexpressed His-CGI58 interacts with overexpressed FLAG-PNPLA2 or FLAG-PNPLA9 in HEK293T cells. The experiment was performed as in panel C, with IP of FLAG and the addition of FLAG-PNPLA2. WB was performed using anti-His antibody. Note that all panels depict a representative experiment, each repeated at least 3 times.