Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1 β-induced chronic inflammation
Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1 β-induced chronic inflammation
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DOI：
10.1038/labinvest.2014.11
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发表时间：
2014-05-01
影响因子：
5
通讯作者：
Kleemann, Robert
中科院分区：
文献类型：
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作者：
Liang, Wen;Lindeman, Jan H.;Kleemann, Robert
导致非酒精性脂肪性肝炎 (NASH) 发展的慢性炎症成分的性质尚不清楚，可能的炎症触发因素尚未得到系统研究。我们研究了炎症的非代谢触发因素（脂多糖 (LPS)、白细胞介素 1 β (IL-1 β)，通过缓释微型泵给药）和代谢饮食触发因素（碳水化合物、胆固醇）对轻度肝脂肪变性 (BS) 进展为 NASH 的影响。喂食高脂饮食 (HFD) 的转基因 APOE3*Leiden.huCETP (APOE3L.CETP) 小鼠在 10 周后出现 BS。然后，炎症触发因素叠加或不叠加（对照）六周以上。对小鼠肝脏进行了分析，特别强调炎症标志，这些标志是在有或没有 NASH 的人类肝脏活检中定义的。 HFD 治疗的对照小鼠的肝脏仍然存在脂肪变性，并且没有进展为 NASH。所有四种炎症触发物均显着且可比地激活肝核因子-κ B (NF-κ B)（>= 5 倍）。然而，HFD + LPS 或 HFD + IL-1 beta 不会诱导 NASH 样表型，并且导致肝内几乎全部是单核细胞积聚。相比之下，接受代谢触发治疗的小鼠则出现 NASH，其特征是脂肪变性增强、肝细胞肥大以及形成含有髓过氧化物酶阳性粒细胞（中性粒细胞）和单核细胞的混合型炎症灶，基本上与人类 NASH 中观察到的一样。代谢诱导剂的具体作用是促炎转录因子激活蛋白-1 (AP-1) 的激活、中性粒细胞浸润以及与人类 NASH 相关的危险因素的诱导，即血脂异常（由胆固醇引起）和胰岛素抵抗（由碳水化合物引起）。总之，HFD 喂养后激活 NF-κ B 本身（LPS、IL-1 beta）并不会促进从 BS 向 NASH 的转变。 HFD 喂养后代谢诱发的炎症会诱导额外的炎症成分（中性粒细胞、AP-1 途径）并导致 NASH。
The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1 beta (IL-1 beta), administered by slow-release minipumps) and metabolic dietary triggers (carbohydrate, cholesterol) of inflammation on the progression of bland liver steatosis (BS) to NASH. Transgenic APOE3*Leiden.huCETP (APOE3L.CETP) mice fed a high-fat diet (HFD) developed BS after 10 weeks. Then, inflammatory triggers were superimposed or not (control) for six more weeks. Mouse livers were analyzed with particular emphasis on hallmarks of inflammation which were defined in human liver biopsies with and without NASH. Livers of HFD-treated control mice remained steatotic and did not progress to NASH. All four inflammatory triggers activated hepaticnuclearfactor-kappa B (NF-kappa B) significantly and comparably (>= 5-fold). However, HFD+ LPS or HFD + IL-1 beta did not induce a NASH-like phenotype and caused intrahepatic accumulation of almost exclusively mononuclear cells. By contrast, mice treated with metabolic triggers developed NASH, characterized by enhanced steatosis, hepatocellular hypertrophy, and formation of mixed-type inflammatory foci containing myeloperoxidase-positive granulocytes (neutrophils) as well as mononuclear cells, essentially as observed in human NASH. Specific for the metabolic inducers was an activation of the proinflammatory transcription factor activator protein-1 (AP-1), neutrophil infiltration, and induction of risk factors associated with human NASH, that is, dyslipidemia (by cholesterol) and insulin resistance (by carbohydrate). In conclusion, HFD feeding followed by NF-kappa B activation per se (LPS, IL-1 beta) does not promote the transition from BS to NASH. HFD feeding followed by metabolically evoked inflammation induces additional inflammatory components (neutrophils, AP-1 pathway) and causes NASH.