ADAR1 Controls Macrophage Scavenging and Lipid-Buffering Programs in Metabolic Tissues.

Area of Science:

• Molecular Biology
• Immunology
• Metabolic Disease Research

Background:

• Adenosine deaminase acting on RNA 1 (ADAR1) is known for its role in innate immunity.
• Its broader functions in macrophages, particularly in metabolic regulation, are not well understood.

Purpose of the Study:

• To investigate the expression and function of ADAR1 in macrophages.
• To explore ADAR1's role in metabolic disease progression and adaptation.

Main Methods:

• Systematic profiling of ADAR1 expression in human immune cells.
• Analysis of ADAR1's isoform-specific binding and editing of macrophage targets.
• Macrophage-specific ADAR1 ablation in 3D human liver spheroids under metabolic stress.
• Investigation of ADAR1 regulation by free fatty acids in adipose tissue.

Main Results:

• ADAR1 is highly expressed in macrophages, with specific isoforms regulating key functions like lipid metabolism and proliferation.
• ADAR1 levels dynamically change during metabolic disease progression.
• Macrophage ADAR1 deficiency exacerbates lipid accumulation under metabolic stress.
• Free fatty acids upregulate ADAR1 in adipose tissue macrophages after weight loss.

Conclusions:

• ADAR1 plays a significant, previously unrecognized role in macrophage lipid buffering, scavenging, and proliferation.
• ADAR1 is a key regulator of macrophage adaptation in metabolic diseases, extending its function beyond immunity.