Lipid Droplet-Associated Hydrolase Mobilizes Stores of Liver X Receptor Sterol Ligands and Protects Against Atherosclerosis

Authors

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
Antoni Paul

Publication Date

8-2-2024

Journal

Nature Communications

DOI

10.1038/s41467-024-50949-y

PMID

39095402

PMCID

PMC11297204

PubMedCentral® Posted Date

8-2-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Atherosclerosis, Liver X Receptors, Mice, Male, Ligands, Female, Lipid Droplets, Mice, Knockout, Macrophages, Sterols, Foam Cells, Mice, Transgenic, Mice, Inbred C57BL, Humans, Plaque, Atherosclerotic, Macrophage Activation, Sterol Esterase

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.

Comments

Associated Data