title: Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-Induced Macrophage Cell Death through Enhancing Ceramide Production.
abstract: Macrophages play a critical role in obesity-associated chronic inflammation and disorders. However, the molecular mechanisms underlying the response of macrophages to elevated fatty acids (FAs) and their contribution to metabolic inflammation in obesity remain to be fully elucidated. In this article, we report a new mechanism by which dietary FAs, in particular, saturated FAs (sFAs), are able to directly trigger macrophage cell death. We demonstrated that excess sFAs, but not unsaturated FAs, induced the production of cytotoxic ceramides (Cers) in macrophage cell lines. Most importantly, expression of adipose FA binding protein (A-FABP) in macrophages facilitated metabolism of excess sFAs for Cer synthesis. Inhibition or deficiency of A-FABP in macrophage cell lines decreased sFA-induced Cer production, thereby resulting in reduced cell death. Furthermore, we validated the role of A-FABP in promoting sFA-induced macrophage cell death with primary bone marrow-derived macrophages and high-fat diet-induced obese mice. Altogether, our data reveal that excess dietary sFAs may serve as direct triggers in induction of Cer production and macrophage cell death through elevated expression of A-FABP, thus establishing A-FABP as a new molecular sensor in triggering macrophage-associated sterile inflammation in obesity.
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202.
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202.
authors.forename: Enyu
authors.initials: E
authors.lastname: Rao
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202.
authors.forename: Jun
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202.
authors.forename: Jiaqing
authors.initials: J
authors.lastname: Hao
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Sun
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912.
authors.forename: Shujun
authors.initials: S
authors.lastname: Liu
authors.affiliation: Hartford Healthcare Cancer Institute, Hartford, CT 06103; and.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sauter
authors.affiliation: College of Biological Sciences, University of Minnesota, Minneapolis, MN 55455.
authors.forename: David A
authors.initials: DA
authors.lastname: Bernlohr
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912.
authors.forename: Margot P
authors.initials: MP
authors.lastname: Cleary
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202.
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202; b.li@louisville.edu.
authors.forename: Bing
authors.initials: B
authors.lastname: Li
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D002518:Ceramides / Q000096:biosynthesis*; D059305:Diet, High-Fat; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D005227:Fatty Acids / Q000009:adverse effects*; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D008264:Macrophages / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009765:Obesity / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D002518:Ceramides; C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids