Institute of Life Science, Swansea University Medical School, Swansea University, Swansea, UK.
The Francis Crick Institute, London, UK.
Nat Commun. 2021 Feb 22;12(1):1209. doi: 10.1038/s41467-021-21461-4.
Fructose intake has increased substantially throughout the developed world and is associated with obesity, type 2 diabetes and non-alcoholic fatty liver disease. Currently, our understanding of the metabolic and mechanistic implications for immune cells, such as monocytes and macrophages, exposed to elevated levels of dietary fructose is limited. Here, we show that fructose reprograms cellular metabolic pathways to favour glutaminolysis and oxidative metabolism, which are required to support increased inflammatory cytokine production in both LPS-treated human monocytes and mouse macrophages. A fructose-dependent increase in mTORC1 activity drives translation of pro-inflammatory cytokines in response to LPS. LPS-stimulated monocytes treated with fructose rely heavily on oxidative metabolism and have reduced flexibility in response to both glycolytic and mitochondrial inhibition, suggesting glycolysis and oxidative metabolism are inextricably coupled in these cells. The physiological implications of fructose exposure are demonstrated in a model of LPS-induced systemic inflammation, with mice exposed to fructose having increased levels of circulating IL-1β after LPS challenge. Taken together, our work underpins a pro-inflammatory role for dietary fructose in LPS-stimulated mononuclear phagocytes which occurs at the expense of metabolic flexibility.
果糖的摄入量在整个发达世界都大幅增加，与肥胖、2 型糖尿病和非酒精性脂肪肝疾病有关。目前，我们对暴露于高水平饮食果糖的免疫细胞（如单核细胞和巨噬细胞）的代谢和机制影响的理解是有限的。在这里，我们表明，果糖重新编程细胞代谢途径，有利于谷氨酰胺分解和氧化代谢，这是支持 LPS 处理的人单核细胞和小鼠巨噬细胞中炎症细胞因子产生增加所必需的。果糖依赖性 mTORC1 活性增加驱动 LPS 反应中促炎细胞因子的翻译。用果糖处理的 LPS 刺激的单核细胞严重依赖氧化代谢，并且对糖酵解和线粒体抑制的反应性降低，这表明这些细胞中的糖酵解和氧化代谢是不可分割的。在 LPS 诱导的全身炎症模型中，果糖暴露的生理意义得到了证明，暴露于果糖的小鼠在 LPS 挑战后循环中 IL-1β 的水平增加。总之，我们的工作支持了饮食果糖在 LPS 刺激的单核吞噬细胞中的促炎作用，这种作用是以代谢灵活性为代价的。
