Hyperresponsivity to Low-Dose Endotoxin during Progression to Nonalcoholic Steatohepatitis Is Regulated by Leptin-Mediated Signaling
Hyperresponsivity to Low-Dose Endotoxin during Progression to Nonalcoholic Steatohepatitis Is Regulated by Leptin-Mediated Signaling
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DOI：
10.1016/j.cmet.2012.05.012
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发表时间：
2012-07-03
期刊：
影响因子：
29
通讯作者：
Nakajima, Atsushi
中科院分区：
文献类型：
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作者：
Imajo, Kento;Fujita, Koji;Nakajima, Atsushi
虽然细菌内毒素，如脂多糖（LPS），在非酒精性脂肪性肝炎（NASH）的发病机制中起着关键作用，但这种发病机制的详细机制仍不清楚。在这里，我们证明了通过瘦素介导的信号传导上调CD 14对于NASH进展过程中对内毒素的高反应性至关重要。在高脂饮食（HFD）诱导的脂肪变性小鼠中观察到枯否细胞中CD 14的上调和对低剂量LPS的高反应性，但在普通饲料喂养的对照小鼠中没有观察到。对低剂量LPS的高反应性导致加速NASH进展，包括肝脏炎症和纤维化。瘦素通过STAT 3信号传导增加了小鼠肝脏中CD 14的表达，导致对低剂量LPS的高反应性，但没有脂肪变性。相比之下，在瘦素缺乏的ob/ob小鼠中观察到肝脏CD 14表达的显著降低，尽管存在严重的脂肪变性。我们的研究结果表明，肥胖诱导的瘦素通过增强对内毒素的反应性在NASH进展中起着至关重要的作用，我们提出了细菌介导的NASH进展的机制。
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.