Integrated Cardio Metabolic Center, Department of Medicine, Karolinska Institutet, 141 57 Huddinge, Sweden.
Université Côte d'Azur, Inserm U1065, C3M, Team Cellular and Molecular Physiopathology of Obesity, 06000 Nice, France.
Sci Transl Med. 2020 Feb 26;12(532). doi: 10.1126/scitranslmed.aaw9709.
Obesity and insulin resistance are risk factors for nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide. Because no approved medication nor an accurate and noninvasive diagnosis is currently available for NAFLD, there is a clear need to better understand the link between obesity and NAFLD. Lipid accumulation during obesity is known to be associated with oxidative stress and inflammatory activation of liver macrophages (LMs). However, we show that although LMs do not become proinflammatory during obesity, they display signs of oxidative stress. In livers of both humans and mice, antioxidant nuclear factor erythroid 2-related factor 2 (NRF2) was down-regulated with obesity and insulin resistance, yielding an impaired response to lipid accumulation. At the molecular level, a microRNA-targeting NRF2 protein, , was elevated in the livers of obese insulin-resistant humans and mice, and specific silencing of in murine and human LMs was sufficient to restore NRF2 protein expression and the antioxidant response. These results highlight the pathological role of LMs and their therapeutic potential to restore the impaired endogenous antioxidant response in obesity-associated NAFLD.
肥胖和胰岛素抵抗是导致非酒精性脂肪性肝病（NAFLD）的危险因素，NAFLD 是全球最常见的慢性肝病。由于目前尚无针对 NAFLD 的批准药物或准确、非侵入性的诊断方法，因此需要更好地了解肥胖与 NAFLD 之间的联系。已知肥胖期间的脂质积累与氧化应激和肝巨噬细胞（LMs）的炎症激活有关。然而，我们发现，尽管 LMs 在肥胖期间不会变得促炎，但它们显示出氧化应激的迹象。在肥胖和胰岛素抵抗的人类和小鼠肝脏中，抗氧化核因子红细胞 2 相关因子 2（NRF2）被下调，导致对脂质积累的反应受损。在分子水平上，一种针对 NRF2 蛋白的 microRNA 被上调在肥胖胰岛素抵抗的人类和小鼠肝脏中，并且在小鼠和人 LMs 中特异性沉默足以恢复 NRF2 蛋白表达和抗氧化反应。这些结果强调了 LMs 的病理作用及其在恢复肥胖相关 NAFLD 中受损内源性抗氧化反应方面的治疗潜力。
