Zhang Yuwen, Rao Enyu, Zeng Jun, Hao Jiaqing, Sun Yanwen, Liu Shujun, Sauter Edward R, Bernlohr David A, Cleary Margot P, Suttles Jill, Li Bing
Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202.
The Hormel Institute, University of Minnesota, Austin, MN 55912.
J Immunol. 2017 Jan 15;198(2):798-807. doi: 10.4049/jimmunol.1601403. Epub 2016 Dec 5.
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.
巨噬细胞在肥胖相关的慢性炎症和疾病中起关键作用。然而，巨噬细胞对脂肪酸（FAs）升高的反应及其在肥胖中对代谢性炎症的作用的分子机制仍有待充分阐明。在本文中，我们报道了一种新机制，即膳食脂肪酸，特别是饱和脂肪酸（sFAs），能够直接引发巨噬细胞死亡。我们证明，过量的饱和脂肪酸而非不饱和脂肪酸，可在巨噬细胞系中诱导细胞毒性神经酰胺（Cers）的产生。最重要的是，巨噬细胞中脂肪脂肪酸结合蛋白（A-FABP）的表达促进了过量饱和脂肪酸用于神经酰胺合成的代谢。巨噬细胞系中A-FABP的抑制或缺乏减少了饱和脂肪酸诱导的神经酰胺产生，从而导致细胞死亡减少。此外，我们用原代骨髓来源的巨噬细胞和高脂饮食诱导的肥胖小鼠验证了A-FABP在促进饱和脂肪酸诱导的巨噬细胞死亡中的作用。总之，我们的数据表明，过量的膳食饱和脂肪酸可能通过A-FABP表达升高，作为诱导神经酰胺产生和巨噬细胞死亡的直接触发因素，从而确立A-FABP为引发肥胖中巨噬细胞相关无菌性炎症的新分子传感器。
