Hines Ian N, Milton Jamie, Kremer Michael, Wheeler Michael D
Department of Nutrition Science, East Carolina University, North Carolina, USA.
Department of General and Visceral Surgery, Hospital of Aarau, Aarau, Switzerland.
Med Res Arch. 2022 Oct;10(9). doi: 10.18103/mra.v10i9.3082. Epub 2022 Sep 20.
Tumor necrosis factor -alpha (TNFα) is strongly associated with fatty liver disease (i.e, hepatosteatosis). Cytokine production has been thought of as a consequence of hepatic lipid accumulation which becomes a critical factor in the development of chronic liver pathologies as well as insulin resistance. The purpose of this study was to test the hypothesis that TNFα directly regulates lipid metabolism in liver in the mutant peroxisome-proliferator activated receptor-alpha (PPARα) mouse model with robust hepatic lipid accumulation. At 10 weeks of age, TNFα and TNF receptor 1 expression are increased in livers of PPARα mice compared to wild type. PPARα mice were then crossed with mice lacking the receptor for TNFα receptor 1 (TNFR1). Wild type, PPARα, TNFR1, PPARα x TNFR1 mice were housed on ad-libitum standard chow diet for up to 40 weeks. Increases in hepatic lipid and liver injury and metabolic disruption associated with PPARα ablation were largely blunted when PPARα mice were crossed with TNFR1 mice. These data support the hypothesis that TNFR1 signaling is critical for accumulation of lipid in liver. Therapies that reduce pro-inflammatory responses, namely TNFα, could have important clinical implications to reduce hepatosteatosis and progression of severe liver disease.
肿瘤坏死因子-α（TNFα）与脂肪性肝病（即肝脂肪变性）密切相关。细胞因子的产生被认为是肝脏脂质蓄积的结果，而肝脏脂质蓄积成为慢性肝脏疾病以及胰岛素抵抗发展的关键因素。本研究的目的是在具有大量肝脏脂质蓄积的突变型过氧化物酶体增殖物激活受体-α（PPARα）小鼠模型中，验证TNFα直接调节肝脏脂质代谢这一假说。在10周龄时，与野生型相比，PPARα小鼠肝脏中TNFα和TNF受体1的表达增加。然后将PPARα小鼠与缺乏TNFα受体1（TNFR1）的小鼠杂交。野生型、PPARα、TNFR1、PPARα×TNFR1小鼠自由采食标准饲料长达40周。当PPARα小鼠与TNFR1小鼠杂交时，与PPARα基因敲除相关的肝脏脂质增加、肝损伤和代谢紊乱在很大程度上得到缓解。这些数据支持TNFR1信号传导对肝脏脂质蓄积至关重要这一假说。减少促炎反应（即TNFα）的疗法可能对减少肝脂肪变性和严重肝病的进展具有重要的临床意义。
