Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury
Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury
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DOI：
10.1073/pnas.1820282116
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发表时间：
2019-07-02
影响因子：
11.1
通讯作者：
Uemoto, Shinji
中科院分区：
文献类型：
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作者：
Miyauchi, Tomoyuki;Uchida, Yoichiro;Uemoto, Shinji
肝脏缺血再灌注损伤（IRI）是肝脏外科面临的主要挑战。饮食限制通过增加应激抵抗力来减少肝损伤;然而，潜在的分子机制仍不清楚。我们研究了禁食12小时对小鼠肝脏IRI的预防作用。使用野生型雄性C57 BL/6小鼠中的部分热肝IRI模型。缺血再灌注（IR）对照组在缺血前12 h给予食物和水，IR禁食组在缺血前12 h给予水但不给予食物。在12小时禁食小鼠，血清肝源性酶水平和组织损伤，由于IR强烈抑制。血清β-羟丁酸（BHB）在缺血前和再灌注期间显著升高。上调的BHB通过提高乙酰化组蛋白的水平诱导FOXO 1转录因子表达的增加。抗氧化酶血红素氧合酶1（HO-1），FOXO 1的靶基因，然后增加。自噬活性也增强。禁食12 h可显著降低血清高迁移率族蛋白B1水平，抑制NF-κ B和NLRP 3炎性小体的活化。因此，炎性细胞因子的产生和肝损伤减少。外源性BHB管理或组蛋白去乙酰化酶抑制剂管理到控制喂养小鼠改善肝脏IRI，而FOXO 1抑制剂管理的12小时禁食组加重肝脏IRI。禁食12 h通过增加BHB，上调FOXO 1和HO-1，下调NF-、B和NLRP 3炎性小体，减少炎症反应和凋亡细胞死亡，对肝脏IRI的预防具有有益作用。
Liver ischemia and reperfusion injury (IRI) is a major challenge in liver surgery. Diet restriction reduces liver damage by increasing stress resistance; however, the underlying molecular mechanisms remain unclear. We investigated the preventive effect of 12-h fasting on mouse liver IRI. Partial warm hepatic IRI model in wildtype male C57BL/6 mice was used. The control ischemia and reperfusion (IR) group of mice was given food and water ad libitum, while the fasting IR group was given water but not food for 12 h before ischemic insult. In 12-h fasting mice, serum liver-derived enzyme level and tissue damages due to IR were strongly suppressed. Serum beta-hydroxybutyric acid (BHB) was significantly raised before ischemia and during reperfusion. Up-regulated BHB induced an increment in the expression of FOXO1 transcription factor by raising the level of acetylated histone. Antioxidative enzyme heme oxigenase 1 (HO-1), a target gene of FOXO1, then increased. Autophagy activity was also enhanced. Serum high-mobility group box 1 was remarkably lowered by the 12-h fasting, and activation of NF-kappa B and NLRP3 inflammasome was suppressed. Consequently, inflammatory cytokine production and liver injury were reduced. Exogenous BHB administration or histone deacetylase inhibitor administration into the control fed mice ameliorated liver IRI, while FOXO1 inhibitor administration to the 12-h fasting group exacerbated liver IRI. The 12-h fasting exerted beneficial effects on the prevention of liver IRI by increasing BHB, thus up-regulating FOXO1 and HO-1, and by reducing the inflammatory responses and apoptotic cell death via the down-regulation of NF-.B and NLRP3 inflammasome.