구영화 (Albany Medical College)

한빛사논문

조회61

Albany Medical College

Nat. Commun., 02 August 2024 | https://doi.org/10.1038/s41467-024-50949-y Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis

Young-Hwa Goo ^{1 *}, Janeesh Plakkal Ayyappan ¹, Francis D. Cheeran ¹, Sushant Bangru^2,3,4, Pradip K. Saha ⁵, Paula Baar ⁶, Sabine Schulz ⁶, Todd A. Lydic ⁷, Bernhard Spengler ^6,8, Andreas H. Wagner ⁹, Auinash Kalsotra ^2,3,4,10, Vijay K. Yechoor ¹¹ & Antoni Paul^{1 *}

¹Department of Molecular and Cellular Physiology, Albany Medical College, Albany, NY, USA.
²Department of Biochemistry, University of Illinois, UrbanaChampaign, IL, USA.
³Cancer Center@Illinois, University of Illinois, Urbana-Champaign, IL, USA.
⁴Carl R. Woese Institute for Genomic Biology, University of Illinois, Urbana-Champaign, IL, USA.
⁵Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
⁶Institute of Inorganic and Analytical Chemistry, Justus Liebig University Giessen, Giessen, Germany.
⁷Department of Physiology, Michigan State University, East Lansing, MI, USA.
⁸TransMIT GmbH, Center for Mass Spectrometric Developments, Giessen, Germany.
⁹Department of Cardiovascular Physiology, Heidelberg University, Heidelberg, Germany.
¹⁰Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, IL, USA.
¹¹Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

^*Corresponding authors: correspondence to Young-Hwa Goo or Antoni Paul

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.

논문정보

형식Research article
게재일2024년 08월 (BRIC 등록일 2024-08-14)
연구진국외 연구진
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