Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis.
Butyrate-producing probiotics reduce nonalcoholic fatty liver disease progression in rats: new insight into the probiotics for the gut-liver axis.
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DOI：
10.1371/journal.pone.0063388
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Watanabe T
中科院分区：
文献类型：
--
作者：
Endo H;Niioka M;Kobayashi N;Tanaka M;Watanabe T
非酒精性脂肪性肝病(NAFLD)包括单纯性脂肪变性、非酒精性脂肪性肝炎(NASH)、纤维化、肝硬变和肝细胞癌。肠源性内毒素在NAFLD的发生发展过程中起重要作用。通过建立胆碱缺乏/L-氨基酸限定饮食诱导的非酒精性脂肪肝大鼠模型，我们研究了丁酸益生菌Miyairi588能否阻止从脂肪变性到肝癌的病理生理变化的进展。体内实验表明，Miyairi 588治疗可减少CDAA饮食诱导的肝脏脂肪沉积，并显著改善甘油三酯含量、胰岛素抵抗、血清内毒素水平和肝脏炎症指标。我们还发现，Miyairi 588显著增加了肝脏5‘-单磷酸活化蛋白激酶(AMPK)和AKT的激活，以及脂肪生成或脂解相关蛋白的表达。Miyairi 588还改善了CDAA饮食诱导的去局部化，并显著降低了CDAA饮食喂养的大鼠肠道紧密连接蛋白oconula occluden-1和occludin的表达。此外，Miyairi 588处理的大鼠还显示出显著的诱导核因子红系2相关因子2(Nrf2)及其靶向抗氧化酶，从而抑制肝脏的氧化应激。体外研究表明，丁酸钠(NAB)处理也激活了AMPK和AKT，并通过阻止泛素化而增强了Nrf2的表达，从而延长了Nrf2蛋白的半衰期。药理学研究和siRNA敲除实验表明，NAB介导的AMPK激活诱导了Sirtuin 1的磷酸化和核转位，导致哺乳动物TOR复合体2的组装增加和AKT在Ser473处的磷酸化，进而诱导Nrf2的表达和激活。这些有利的变化导致肝纤维沉积、GST-P阳性病灶的形成和肝癌发生的明显减少。我们的数据清楚地表明，益生菌Miyairi 588在预防NAFLD进展方面具有有益的效果。
Nonalcoholic fatty liver disease (NAFLD) includes simple steatosis, nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The gut-derived endotoxin plays an essential role in the pathophysiological development and progression of NAFLD. By using rat models of choline-deficient/L-amino acid-defined (CDAA)-diet-induced NAFLD, we examined whether MIYAIRI 588–a butyrate-producing probiotic – prevents the progression of pathophysiological changes from steatosis to hepatocarcinogenesis. In vivo experiments showed that treatment with MIYAIRI 588 reduced CDAA-diet-induced hepatic lipid deposition and significantly improved the triglyceride content, insulin resistance, serum endotoxin levels, and hepatic inflammatory indexes. We also found that MIYAIRI 588 substantially increased the activation of hepatic adenosine 5′-monophosphate-activated protein kinase (AMPK) and AKT and the expression of lipogenesis- or lipolysis-related proteins. MIYAIRI 588 also improved CDAA-diet-induced delocalization and substantially decreased the expression of the tight-junction proteins intestinal zonula occluden-1 and occludin in CDAA-diet-fed rats. Further, the MIYAIRI 588-treated rats also showed remarkable induction of nuclear factor erythoid 2-related factor 2 (Nrf2) and its targeted antioxidative enzymes, which suppressed hepatic oxidative stress. In vitro studies revealed that treatment with sodium butyrate (NaB) also activated AMPK and AKT and enhanced Nrf2 expression by precluding ubiquitination, thereby increasing the half-life of the Nrf2 protein. Pharmacological studies and siRNA knockdown experiments showed that NaB-mediated AMPK activation induced the phosphorylation and nuclear translocation of Sirtuin 1, leading to the increased assembly of mammalian TOR complex 2 and phosphorylation of AKT at Ser473 and subsequent induction of Nrf2 expression and activation. These favorable changes caused an obvious decrease in hepatic fibrous deposition, GST-P-positive foci development, and hepatocarcinogenesis. Our data clearly established that the probiotic MIYAIRI 588 has beneficial effects in the prevention of NAFLD progression.
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影响因子：
13.5
作者：
García-Trevijano, ER;Iraburu, MJ;Rojkind, M
通讯作者：
Rojkind, M
影响因子：
5.3
作者：
Kobayashi, Makoto;Li, Li;Yamamoto, Masayuki
通讯作者：
Yamamoto, Masayuki
影响因子：
10.4
作者：
Endo, Hitoshi;Sugioka, Yoshihiko;Nakagi, Yoshihiko;Saijo, Yasuaki;Yoshida, Takahiko
通讯作者：
Yoshida, Takahiko
DOI：
10.1152/ajpendo.00253.2007
发表时间：
2008-04-01
影响因子：
5.1
作者：
Koketsu, Yuko;Sakoda, Hideyuki;Asano, Tomoichiro
通讯作者：
Asano, Tomoichiro
影响因子：
25.7
作者：
Bergheim, Ina;Weber, Synia;Bischoff, Stephan C.
通讯作者：
Bischoff, Stephan C.