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Cell Metab:脂多糖促进NASH机制探明

来源:生物谷 2012-07-12 15:50

细菌内毒素,如脂多糖(LPS)在非酒精性脂肪性肝炎(NASH,nonalcoholic steatohepatitis)的发病过程中发挥关键作用,但其发病机理尚不清楚。近日,日本研究人员发现,瘦素信号途径调节的CD14的上调在其中发挥重要作用。相关论文发表在近期的Cell Metabolism杂志上。

高脂喂养的脂肪发生病变的小鼠Kupffer细胞中CD14上调,对低剂量LPS的反应敏感性提高,正常饲料喂养的小鼠无此现象。对于低剂量的LPS敏感性的提高可加速NASH的发病过程,包括肝脏炎症和纤维化。

给喂养正常饲料的小鼠注射瘦素,肝脏CD14的表达量增加,对低剂量LPS的敏感性增加,但无脂肪变性。瘦素缺乏的ob/ob小鼠的CD14表达量显著降低,但却发生了严重的脂肪变性。

结果表明,肥胖诱导产生的瘦素在NASH的发病过程中发挥关键作用,因瘦素可增强对于内毒素的反应敏感性。(生物谷Bioon.com)

Hyperresponsivity to Low-Dose Endotoxin during Progression to Nonalcoholic Steatohepatitis Is Regulated by Leptin-Mediated Signaling

Kento Imajo1, Koji Fujita1, Masato Yoneda1, Yuichi Nozaki1, Yuji Ogawa1, Yoshiyasu Shinohara1, Shingo Kato1, Hironori Mawatari1, Wataru Shibata1, Hiroshi Kitani2, Kenichi Ikejima3, Hiroyuki Kirikoshi1, Noriko Nakajima4, Satoru Saito1, Shiro Maeyama5, Sumio Watanabe3, Koichiro Wada6, Atsushi Nakajima

Although bacterial endotoxin, such as lipopolysaccharide (LPS), plays a key role in the pathogenesis of nonalcoholic steatohepatitis (NASH), detailed mechanisms of this pathogenesis remain unclear. Here, we demonstrate that upregulation of CD14 by leptin-mediated signaling is critical to hyperreactivity against endotoxin during NASH progression. Upregulation of CD14 in Kupffer cells and hyperreactivity against low-dose LPS were observed in high-fat diet (HFD)-induced steatosis mice, but not chow-fed-control mice. Hyperresponsivity against low-dose LPS led to accelerated NASH progression, including liver inflammation and fibrosis. Administering leptin in chow-fed mice caused increased hepatic expression of CD14 via STAT3 signaling, resulting in hyperreactivity against low-dose LPS without steatosis. In contrast, a marked decrease in hepatic CD14 expression was observed in leptin-deficient ob/ob mice, despite severe steatosis. Our results indicate that obesity-induced leptin plays a crucial role in NASH progression via enhanced responsivity to endotoxin, and we propose a mechanism of bacteria-mediated progression of NASH.

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