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The lipase cofactor CGI58 controls placental lipolysis
Jennifer Guerrero-Santoro, … , Valerian E. Kagan, Yoel Sadovsky
Jennifer Guerrero-Santoro, … , Valerian E. Kagan, Yoel Sadovsky
Published May 22, 2023
Citation Information: JCI Insight. 2023;8(10):e168717. https://doi.org/10.1172/jci.insight.168717.
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Research Article Reproductive biology

The lipase cofactor CGI58 controls placental lipolysis

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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

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Figure 1

The function of Pnpla2 and Cgi58 in the placenta.

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The function of Pnpla2 and Cgi58 in the placenta.
(A and B) The expressi...
(A and B) The expression of Pnpla2 and Cgi58 RNA (A): n = 3, *P < 0.05, ANOVA with post hoc Tukey’s test; and protein (B) across the second half of mouse pregnancy (n = 5). DKO, double KO. (C) The effect of ablation of Atgl, Cgi58, or both on placental lipid accumulation at E17.5, monitored using Oil Red O staining for neutral lipids, performed as detailed in Methods. WT, wild-type. (D) The accumulation of LDs in the E17.5 mouse placental labyrinth (left, n = 48–63) or TGs (right, n = 3–18) according to mouse genotypes. *P < 0.01, **P < 0.001, ANOVA with post hoc Tukey’s test. (E) The accumulation of LDs in the E17.5 mouse placental labyrinth, analyzed using bright-field microscopy enhancement as descried in Methods. (F) The level of TAG in the mouse placenta in WT and Cgi58-KO placentas, analyzed by MS/MS (n = 10, *P < 0.0001, t test). (G) Immunofluorescence staining of CGI58 (shown in red), with nuclei stained with 4′,6-diamidino-2-phenylindole (DAPI) (blue), in human placental villi. (H) Knockdown of CGI58 in PHT cells, stained with boron dipyrromethene difluoride 493/503 (BODIPY) (green) for LDs and DAPI (blue) for nuclei.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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