Schweitzer S C, Reding A M, Patton H M, Sullivan T P, Stubbs C E, Villalobos-Menuey E, Huber S A, Newell M K
Colorado University Institute of Bioenergetics, University of Colorado, Colorado Springs, CO, USA.
J Lipid Res. 2006 Nov;47(11):2525-37. doi: 10.1194/jlr.M600329-JLR200. Epub 2006 Aug 16.
Although the immune system, inflammation, and cellular metabolism are linked to diseases associated with dyslipidemias, the mechanism(s) remain unclear. To determine whether there is a mechanistic link between lipid availability and inflammation/immune activation, we evaluated macrophage cell lines incubated under conditions of altered exogenous and endogenous lipid availability. Limiting exogenous lipids results in decreased lysosomal acidity and decreased lysosomal enzymatic activity. Both lysosomal parameters are restored with the addition of oleoyl-CoA, suggesting that fatty acids play a role in the regulation of lysosomal function. Cell surface expression of major histocompatibility complex (MHC)-encoded molecules is also decreased in the absence of exogenous lipids. Additionally, we observe decreased gamma-interferon stimulation of cell surface MHC class II. Using cerulenin to limit the endogenous synthesis of fatty acids results in decreased cell surface expression of MHC class II but does not appear to alter lysosomal acidity, suggesting that lysosomal acidity is dependent on exogenous, but not endogenous, fatty acid availability. Testing these conclusions in an in vivo mouse model, we observed statistically significant, diet-dependent differences in lysosomal acidity and MHC class II cell surface expression. Collectively, these data demonstrate a mechanistic link between lipid availability and early events in the immune response.
尽管免疫系统、炎症和细胞代谢与血脂异常相关疾病存在联系，但其机制仍不清楚。为了确定脂质可用性与炎症/免疫激活之间是否存在机制联系，我们评估了在外源和内源性脂质可用性改变的条件下培养的巨噬细胞系。限制外源脂质会导致溶酶体酸度降低和溶酶体酶活性降低。添加油酰辅酶A后，这两个溶酶体参数均得以恢复，表明脂肪酸在溶酶体功能调节中发挥作用。在缺乏外源脂质的情况下，主要组织相容性复合体（MHC）编码分子的细胞表面表达也会降低。此外，我们观察到γ干扰素对细胞表面MHC II类分子的刺激作用减弱。使用浅蓝菌素限制脂肪酸的内源性合成会导致MHC II类分子的细胞表面表达降低，但似乎不会改变溶酶体酸度，这表明溶酶体酸度依赖于外源脂肪酸可用性，而非内源性脂肪酸可用性。在体内小鼠模型中验证这些结论时，我们观察到溶酶体酸度和MHC II类分子细胞表面表达存在统计学上显著的、依赖于饮食的差异。总体而言，这些数据证明了脂质可用性与免疫反应早期事件之间的机制联系。
