Alcohol-Induced Glycolytic Shift in Alveolar Macrophages Is Mediated by Hypoxia-Inducible Factor-1 Alpha.
Alcohol-Induced Glycolytic Shift in Alveolar Macrophages Is Mediated by Hypoxia-Inducible Factor-1 Alpha.
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肺泡巨噬细胞中酒精诱导的糖酵解转移是由缺氧诱导因子-1α介导的。
DOI：
10.3389/fimmu.2022.865492
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发表时间：
2022
影响因子：
7.3
通讯作者：
Yeligar, Samantha M.
中科院分区：
文献类型：
--
作者：
Morris, Niya L.;Michael, David N.;Crotty, Kathryn M.;Chang, Sarah S.;Yeligar, Samantha M.
过量饮酒会增加呼吸道感染的风险，部分原因是肺泡巨噬细胞（AM）吞噬能力受损。以前，我们表明，慢性乙醇（EtOH）暴露导致线粒体紊乱和减少氧化磷酸化AM。由于氧化磷酸化需要满足吞噬作用的能量需求，因此EtOH介导的氧化磷酸化减少可能导致AM吞噬作用受损。过氧化物酶体增殖物激活受体γ（PPARγ）配体吡格列酮（PIO）治疗可改善乙醇介导的氧化磷酸化降低。在其他模型中，缺氧诱导因子-1 α（HIF-1α）已被证明介导从氧化磷酸化到糖酵解的转换;然而，HIF-1α在慢性EtOH介导的AM紊乱中的作用尚未探讨。我们假设AM在慢性乙醇暴露后发生了从氧化磷酸化到糖酵解表型的代谢转变。此外，我们推测HIF-1α是这种代谢转换的关键介质。为了测试这些假设，从慢性EtOH消耗的小鼠模型中分离原代小鼠AM（mAM），并将小鼠AM细胞系（MH-S）体外暴露于EtOH。通过qRT-PCR和蛋白质印迹法测定HIF-1α、葡萄糖转运蛋白（Glut 1和4）和糖酵解途径组分（Pfkfb 3和PKM 2）的表达。进行乳酸水平（乳酸测定）、细胞能量表型（细胞外通量分析仪）、糖酵解应激试验（细胞外通量分析仪）和吞噬功能（荧光显微镜）。EtOH暴露增加了HIF-1α、Glut 1、Glut 4、Pfkfb 3和PKM 2的表达，并使AM转变为糖酵解表型。通过氯化钴处理的HIF-1α在体外的药理学稳定模拟了乙醇诱导的AM紊乱（糖酵解增加和吞噬能力降低）。此外，PIO处理降低了HIF-1α水平，并逆转了EtOH暴露后的糖酵解转变。这些研究支持HIF-1α在过度饮酒过程中介导AM能量代谢糖酵解转变中的关键作用。
Excessive alcohol use increases the risk of developing respiratory infections partially due to impaired alveolar macrophage (AM) phagocytic capacity. Previously, we showed that chronic ethanol (EtOH) exposure led to mitochondrial derangements and diminished oxidative phosphorylation in AM. Since oxidative phosphorylation is needed to meet the energy demands of phagocytosis, EtOH mediated decreases in oxidative phosphorylation likely contribute to impaired AM phagocytosis. Treatment with the peroxisome proliferator-activated receptor gamma (PPARγ) ligand, pioglitazone (PIO), improved EtOH-mediated decreases in oxidative phosphorylation. In other models, hypoxia-inducible factor-1 alpha (HIF-1α) has been shown to mediate the switch from oxidative phosphorylation to glycolysis; however, the role of HIF-1α in chronic EtOH mediated derangements in AM has not been explored. We hypothesize that AM undergo a metabolic shift from oxidative phosphorylation to a glycolytic phenotype in response to chronic EtOH exposure. Further, we speculate that HIF-1α is a critical mediator of this metabolic switch. To test these hypotheses, primary mouse AM (mAM) were isolated from a mouse model of chronic EtOH consumption and a mouse AM cell line (MH-S) were exposed to EtOH in vitro. Expression of HIF-1α, glucose transporters (Glut1 and 4), and components of the glycolytic pathway (Pfkfb3 and PKM2), were measured by qRT-PCR and western blot. Lactate levels (lactate assay), cell energy phenotype (extracellular flux analyzer), glycolysis stress tests (extracellular flux analyzer), and phagocytic function (fluorescent microscopy) were conducted. EtOH exposure increased expression of HIF-1α, Glut1, Glut4, Pfkfb3, and PKM2 and shifted AM to a glycolytic phenotype. Pharmacological stabilization of HIF-1α via cobalt chloride treatment in vitro mimicked EtOH-induced AM derangements (increased glycolysis and diminished phagocytic capacity). Further, PIO treatment diminished HIF-1α levels and reversed glycolytic shift following EtOH exposure. These studies support a critical role for HIF-1α in mediating the glycolytic shift in energy metabolism of AM during excessive alcohol use.
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影响因子：
4.3
作者：
Sutliff RL;Kang BY;Hart CM
通讯作者：
Hart CM
DOI：
10.1164/rccm.201301-0061oc
发表时间：
2013-09-15
影响因子：
24.7
作者：
Mehta, Ashish J.;Yeligar, Samantha M.;Guidot, David M.
通讯作者：
Guidot, David M.
影响因子：
14.2
作者：
Lee, Kyung Sun;Kim, So Ri;Lee, Yong Chul
通讯作者：
Lee, Yong Chul
影响因子：
4.6
作者：
Del Rey MJ;Valín Á;Usategui A;García-Herrero CM;Sánchez-Aragó M;Cuezva JM;Galindo M;Bravo B;Cañete JD;Blanco FJ;Criado G;Pablos JL
通讯作者：
Pablos JL
影响因子：
8.8
作者：
Miska, Jason;Lee-Chang, Catalina;Lesniak, Maciej S.
通讯作者：
Lesniak, Maciej S.