Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids.
Alcohol inhibits T-cell glucose metabolism and hepatitis in ALDH2-deficient mice and humans: roles of acetaldehyde and glucocorticoids.
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DOI：
10.1136/gutjnl-2018-316221
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发表时间：
2019-07
期刊：
影响因子：
24.5
通讯作者：
Gao B
中科院分区：
文献类型：
--
作者：
Gao Y;Zhou Z;Ren T;Kim SJ;He Y;Seo W;Guillot A;Ding Y;Wu R;Shao S;Wang X;Zhang H;Wang W;Feng D;Xu M;Han E;Zhong W;Zhou Z;Pacher P;Niu J;Gao B
乙醛脱氢酶2(ALDH2)是肝脏中乙醛解毒的关键酶，在人体内以活性和非活性两种形式存在。ALDH2不活跃的个体在饮酒后积累乙醛。然而，乙醛如何影响T细胞性肝炎仍不清楚。野生型(WT)和ALDH2基因敲除(ALDH2-/-)小鼠采用慢性乙醇喂养和刀豆蛋白A(ConA)诱导的T细胞性肝炎模型。体外研究乙醛对T细胞葡萄糖代谢的影响。受试者被招募进行狂饮，并测量血浆皮质醇和皮质酮。乙醇喂养加重了WT小鼠ConA诱导的肝炎，但出人意料地减轻了ALDH2-/-小鼠的肝炎，尽管ALDH2-/-小鼠的乙醛水平更高。与WT小鼠相比，乙醇喂养的ALDH2-/-小鼠的ConA注射后血清细胞因子及其在肝脏中的下游信号的升高有所减弱。在体外，乙醛可抑制ConA诱导的小鼠脾细胞中几种细胞因子的产生，但不影响它们的mRNAs。乙醛还可以减少植物血凝素刺激的人外周淋巴细胞中干扰素-γ的产生。从机制上讲，乙醛通过抑制有氧糖酵解相关的信号通路来干扰T细胞的葡萄糖代谢。最后，与WT小鼠相比，酒精喂养的ALDH2-/-小鼠的血清皮质酮水平更高，皮质酮是一种众所周知的抑制有氧糖酵解的因素。阻断皮质酮可部分恢复乙醇喂养的ALDH2-/-小鼠ConA介导的肝炎。急性饮酒使受试者血浆皮质醇和皮质酮水平升高，ALDH2非活动者的水平高于ALDH2活动者。ALDH2缺乏与饮酒后乙醛和糖皮质激素升高有关，从而抑制T细胞激活和肝炎。
Aldehyde dehydrogenase 2 (ALDH2), a key enzyme to detoxify acetaldehyde in the liver, exists in both active and inactive forms in humans. Individuals with inactive ALDH2 accumulate acetaldehyde after alcohol consumption. However, how acetaldehyde affects T-cell hepatitis remains unknown. Wild-type (WT) and Aldh2 knockout (Aldh2 -/-) mice were subjected to chronic ethanol feeding and concanavalin A (ConA)-induced T-cell hepatitis. Effects of acetaldehyde on T-cell glucose metabolism were investigated in vitro. Human subjects were recruited for binge drinking and plasma cortisol and corticosterone measurement. Ethanol feeding exacerbated ConA-induced hepatitis in WT mice but surprisingly attenuated it in Aldh2 -/- mice despite higher acetaldehyde levels in Aldh2 -/- mice. Elevation of serum cytokines and their downstream signals in the liver post-ConA injection was attenuated in ethanol-fed Aldh2 -/- mice compared to WT mice. In vitro exposure to acetaldehyde inhibited ConA-induced production of several cytokines without affecting their mRNAs in mouse splenocytes. Acetaldehyde also attenuated interferon-γ production in phytohaemagglutinin-stimulated human peripheral lymphocytes. Mechanistically, acetaldehyde interfered with glucose metabolism in T cells by inhibiting aerobic glycolysis-related signal pathways. Finally, compared to WT mice, ethanol-fed Aldh2 -/- mice had higher levels of serum corticosterone, a well-known factor that inhibits aerobic glycolysis. Blockade of corticosterone partially restored ConA-mediated hepatitis in ethanol-fed Aldh2 -/- mice. Acute alcohol drinking elevated plasma cortisol and corticosterone levels in human subjects with higher levels in those with inactive ALDH2 than those with active ALDH2. ALDH2 deficiency is associated with elevated acetaldehyde and glucocorticoids post-alcohol consumption, thereby inhibiting T-cell activation and hepatitis.
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影响因子：
11
作者：
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通讯作者：
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影响因子：
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作者：
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