Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-Induced Macrophage Cell Death through Enhancing...

Area of Science:

• Immunology
• Metabolic disorders
• Cell biology

Background:

• Macrophages are central to obesity-associated chronic inflammation.
• Mechanisms linking fatty acids (FAs) to macrophage dysfunction in obesity require further elucidation.

Purpose of the Study:

• To investigate how dietary FAs, particularly saturated FAs (SFAs), induce macrophage cell death.
• To identify molecular mechanisms and key proteins involved in SFA-induced macrophage inflammation.

Main Methods:

• Utilized macrophage cell lines and primary bone marrow-derived macrophages.
• Administered excess SFAs and unsaturated FAs.
• Measured ceramide (Cer) production and cell death.
• Assessed the role of adipose fatty acid binding protein (A-FABP) through inhibition and deficiency studies.
• Validated findings in high-fat diet-induced obese mouse models.

Main Results:

• Excess SFAs, but not unsaturated FAs, induced cytotoxic ceramide (Cer) production in macrophages.
• Adipose fatty acid binding protein (A-FABP) expression facilitated SFA metabolism for Cer synthesis.
• Inhibition or deficiency of A-FABP reduced SFA-induced Cer production and macrophage cell death.
• A-FABP was confirmed to promote SFA-induced macrophage cell death in primary cells and obese mice.

Conclusions:

• Excess dietary SFAs directly trigger macrophage cell death by inducing Cer production.
• Elevated A-FABP expression in macrophages acts as a sensor for excess SFAs, promoting Cer synthesis and cell death.
• A-FABP is identified as a novel molecular player in initiating macrophage-associated sterile inflammation in obesity.