Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis

Young-Hwa Goo (), Janeesh Plakkal Ayyappan, Francis D. Cheeran, Sushant Bangru, Pradip K. Saha, Paula Baar, Sabine Schulz, Todd A. Lydic, Bernhard Spengler, Andreas H. Wagner, Auinash Kalsotra, Vijay K. Yechoor and Antoni Paul ()
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Young-Hwa Goo: Albany Medical College
Janeesh Plakkal Ayyappan: Albany Medical College
Francis D. Cheeran: Albany Medical College
Sushant Bangru: University of Illinois
Pradip K. Saha: Baylor College of Medicine
Paula Baar: Justus Liebig University Giessen
Sabine Schulz: Justus Liebig University Giessen
Todd A. Lydic: Michigan State University
Bernhard Spengler: Justus Liebig University Giessen
Andreas H. Wagner: Heidelberg University
Auinash Kalsotra: University of Illinois
Vijay K. Yechoor: University of Pittsburgh
Antoni Paul: Albany Medical College

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-50949-y

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