@article{2b6b0bcc9b884a5b8e603cb0bd0a8ad3,
title = "Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis",
abstract = "Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.",
author = "Goo, \{Young Hwa\} and \{Plakkal Ayyappan\}, Janeesh and Cheeran, \{Francis D.\} and Sushant Bangru and Saha, \{Pradip K.\} and Paula Baar and Sabine Schulz and Lydic, \{Todd A.\} and Bernhard Spengler and Wagner, \{Andreas H.\} and Auinash Kalsotra and Yechoor, \{Vijay K.\} and Antoni Paul",
note = "We thank Dr. David A. Hume for providing the promoter and enhancer of the Csf1r gene for the transgenic construct. The knockout mouse strain used for this research project was generated from targeted ES Cells for 1110057K04Rik obtained from the KOMP Repository www.komp.org, a NCRR-NIH supported mouse strain repository (U42-RR024244). ES cells from which this mouse was generated were created by Velocigene from funds provided by the trans-NIH Knock-Out Mouse Project (KOMP) (Grant \# 5U01U01HG004085). Product inquiries can be emailed to
[email protected]. We thank the Roy J. Carver sequencing and genotyping core facilities at the University of Illinois, Urbana-Champaign. Figure\textbackslash{}u00A08 was generated in part using images from Servier Medical Art, under a Creative Commons License CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This research was funded by grants from the American Heart Association (18TPA34230103 to A. Paul and 971847 to Y.-H. Goo); A. Paul was supported in part by the National Institutes of Health (R01DK128972); A. Kalsotra was supported by the National Institutes of Health (R01HL126845, R01AA010154), by the Muscular Dystrophy Association (MDA514335), and by a Chan-Zuckerberg Biohub Chicago Investigator Award; S. Bangru was supported by the NIH Tissue microenvironment training program (T32-EB019944) and Scott Dissertation fellowship from UIUC graduate college. V. Yechoor was supported in part by the National Institutes of Health (R01DK130499) and by the US Department of Veterans Affairs (I01BX002678). B. Spengler received financial support by the Deutsche Forschungsgemeinschaft (Sp314/13-1). We thank Dr. David A. Hume for providing the promoter and enhancer of the Csf1r gene for the transgenic construct. The knockout mouse strain used for this research project was generated from targeted ES Cells for 1110057K04Rik obtained from the KOMP Repository www.komp.org , a NCRR-NIH supported mouse strain repository (U42-RR024244). ES cells from which this mouse was generated were created by Velocigene from funds provided by the trans-NIH Knock-Out Mouse Project (KOMP) (Grant \# 5U01U01HG004085). Product inquiries can be emailed to
[email protected]. We thank the Roy J. Carver sequencing and genotyping core facilities at the University of Illinois, Urbana-Champaign. Figure was generated in part using images from Servier Medical Art, under a Creative Commons License CC BY 4.0 ( https://creativecommons.org/licenses/by/4.0/ ). This research was funded by grants from the American Heart Association (18TPA34230103 to A. Paul and 971847 to Y.-H. Goo); A. Paul was supported in part by the National Institutes of Health (R01DK128972); A. Kalsotra was supported by the National Institutes of Health (R01HL126845, R01AA010154), by the Muscular Dystrophy Association (MDA514335), and by a Chan-Zuckerberg Biohub Chicago Investigator Award; S. Bangru was supported by the NIH Tissue microenvironment training program (T32-EB019944) and Scott Dissertation fellowship from UIUC graduate college. V. Yechoor was supported in part by the National Institutes of Health (R01DK130499) and by the US Department of Veterans Affairs (I01BX002678). B. Spengler received financial support by the Deutsche Forschungsgemeinschaft (Sp314/13-1).",
year = "2024",
month = dec,
doi = "10.1038/s41467-024-50949-y",
language = "English (US)",
volume = "15",
journal = "Nature communications",
issn = "2041-1723",
publisher = "Nature Research",
number = "1",
}