Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
Hepatology. 2020 Sep;72(3):873-891. doi: 10.1002/hep.31390.
Neutrophil infiltration is a hallmark of nonalcoholic steatohepatitis (NASH), but how this occurs during the progression from steatosis to NASH remains obscure. Human NASH features hepatic neutrophil infiltration and up-regulation of major neutrophil-recruiting chemokines (e.g., chemokine [C-X-C motif] ligand 1 [CXCL1] and interleukin [IL]-8). However, mice fed a high-fat diet (HFD) only develop fatty liver without significant neutrophil infiltration or elevation of chemokines. The aim of this study was to determine why mice are resistant to NASH development and the involvement of p38 mitogen-activated protein kinase (p38) activated by neutrophil-derived oxidative stress in the pathogenesis of NASH.
Inflamed human hepatocytes attracted neutrophils more effectively than inflamed mouse hepatocytes because of the greater induction of CXCL1 and IL-8 in human hepatocytes. Hepatic overexpression of Cxcl1 and/or IL-8 promoted steatosis-to-NASH progression in HFD-fed mice by inducing liver inflammation, injury, and p38 activation. Pharmacological inhibition of p38α/β or hepatocyte-specific deletion of p38a (a predominant form in the liver) attenuated liver injury and fibrosis in the HFD -induced NASH model that is associated with strong hepatic p38α activation. In contrast, hepatocyte-specific deletion of p38a in HFD-induced fatty liver where p38α activation is relatively weak exacerbated steatosis and liver injury. Mechanistically, weak p38α activation in fatty liver up-regulated the genes involved in fatty acid β-oxidation through peroxisome proliferator-activated receptor alpha phosphorylation, thereby reducing steatosis. Conversely, strong p38α activation in NASH promoted caspase-3 cleavage, CCAAT-enhancer-binding proteins homologous protein expression, and B cell lymphoma 2 phosphorylation, thereby exacerbating hepatocyte death.
Genetic ablation of hepatic p38a increases simple steatosis but ameliorates oxidative stress-driven NASH, indicating that p38α plays distinct roles depending on the disease stages, which may set the stage for investigating p38α as a therapeutic target for the treatment of NASH.
中性粒细胞浸润是非酒精性脂肪性肝炎（NASH）的一个标志，但在脂肪变性向 NASH 进展过程中，这种情况是如何发生的仍不清楚。人类 NASH 表现为肝内中性粒细胞浸润和主要中性粒细胞募集趋化因子（如趋化因子[C-X-C 基序]配体 1 [CXCL1]和白细胞介素[IL]-8）的上调。然而，给予高脂肪饮食（HFD）的小鼠仅发展为脂肪肝，而没有明显的中性粒细胞浸润或趋化因子升高。本研究旨在确定为什么小鼠对 NASH 发展具有抗性，以及中性粒细胞衍生的氧化应激激活的 p38 丝裂原活化蛋白激酶（p38）在 NASH 发病机制中的参与。
与炎症状态的小鼠肝细胞相比，炎症状态的人肝细胞更有效地吸引中性粒细胞，因为人肝细胞中 CXCL1 和 IL-8 的诱导作用更大。在 HFD 喂养的小鼠中过表达 Cxcl1 和/或 IL-8 通过诱导肝脏炎症、损伤和 p38 激活促进脂肪变性向 NASH 进展。p38α/β 的药理学抑制或肝细胞特异性敲除 p38a（肝脏中的主要形式）减弱了与强烈的肝 p38α 激活相关的 HFD 诱导的 NASH 模型中的肝损伤和纤维化。相反，在 HFD 诱导的脂肪性肝病中，肝细胞特异性敲除 p38a，其中 p38α 激活相对较弱，加剧了脂肪变性和肝损伤。从机制上讲，脂肪变性中的弱 p38α 激活通过过氧化物酶体增殖物激活受体α磷酸化上调参与脂肪酸β氧化的基因，从而减少脂肪变性。相反，NASH 中的强 p38α 激活促进了胱天蛋白酶-3 切割、CCAAT 增强子结合蛋白同源蛋白表达和 B 细胞淋巴瘤 2 磷酸化，从而加剧了肝细胞死亡。
肝细胞 p38a 的基因缺失增加了单纯性脂肪变性，但改善了氧化应激驱动的 NASH，表明 p38α 根据疾病阶段发挥不同的作用，这可能为研究 p38α 作为 NASH 治疗的治疗靶点奠定了基础。
