Liang Wen, Lindeman Jan H, Menke Aswin L, Koonen Debby P, Morrison Martine, Havekes Louis M, van den Hoek Anita M, Kleemann Robert
1] The Netherlands Organization for Applied Scientific Research (TNO), Department of Metabolic Health Research, TNO Metabolic Health Research, Leiden, The Netherlands [2] Departments of Endocrinology and Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Vascular Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Lab Invest. 2014 May;94(5):491-502. doi: 10.1038/labinvest.2014.11. Epub 2014 Feb 24.
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-1β (IL-1β), 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 hepatic nuclear factor-κB (NF-κB) significantly and comparably (≥5-fold). However, HFD+LPS or HFD+IL-1β 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-κB activation per se (LPS, IL-1β) 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.
驱动非酒精性脂肪性肝炎（NASH）发展的慢性炎症成分的本质尚不清楚，可能的炎症触发因素也未得到系统研究。我们研究了非代谢性触发因素（通过缓释微型泵给予的脂多糖（LPS）、白细胞介素-1β（IL-1β））和炎症的代谢性饮食触发因素（碳水化合物、胆固醇）对单纯性肝脂肪变性（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周后出现了BS。然后，再额外六周施加或不施加（对照）炎症触发因素。对小鼠肝脏进行分析，特别关注在有和没有NASH的人类肝脏活检中定义的炎症特征。接受HFD治疗的对照小鼠的肝脏仍为脂肪变性，未进展为NASH。所有四种炎症触发因素均显著且同等程度地激活肝细胞核因子-κB（NF-κB）（≥5倍）。然而，HFD+LPS或HFD+IL-1β并未诱导出NASH样表型，且几乎仅导致肝内单核细胞积聚。相比之下，接受代谢性触发因素治疗的小鼠发展为NASH，其特征为脂肪变性增强、肝细胞肥大，以及形成包含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，这与在人类NASH中观察到的情况基本一致。代谢诱导剂的特异性表现为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喂养后单纯的NF-κB激活（LPS、IL-1β）不会促进从BS向NASH的转变。HFD喂养后由代谢引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。
