1 Institute of Translational Immunology, University Medical Center, Johannes Gutenberg-University , Mainz, Germany .
2 Research Center for Immunotherapy (FZI), University Medical Center, Johannes Gutenberg-University , Mainz, Germany .
Antioxid Redox Signal. 2018 Jan 10;28(2):87-109. doi: 10.1089/ars.2016.6953. Epub 2017 Jul 25.
Nonalcoholic steatohepatitis (NASH) is characterized by steatosis, panlobular inflammation, liver fibrosis, and increased cardiovascular mortality. Dipeptidyl peptidase-4 inhibitors (gliptins) are indirect glucagon-like peptide 1 agonists with antidiabetic and anti-inflammatory activity, used for the treatment of type 2 diabetes. Their potential and underlying mechanisms to treat metabolic liver inflammation and fibrosis as well as the associated vascular dysfunction remain to be explored.
In the methionine/choline-deficient (MCD) diet and Mdr2 models of NASH and liver fibrosis, treatment with sitagliptin and linagliptin significantly decreased parameters of steatosis and inflammation, which was accompanied by suppression of hepatic transcript levels reflecting metabolic inflammation and fibrosis, including SREBP-1c, FAS, TNFα, iNOS, α-SMA, Col1α1, and MMP-12. Moreover, gliptins reduced the number of liver infiltrating CD11bLy6C proinflammatory monocytes/macrophages and liver-resident F4/80 macrophages, with an increase of Ym1 alternative macrophages and (anti-inflammatory) macrophage markers Arg1 and IL-10. This was paralleled by decreased hepatic and aortic reactive oxygen species (ROS) production and NOX-2 mRNA expression, a normalization of endothelial dysfunction, cardiac NADPH oxidase activity, mitochondrial ROS formation, and whole blood oxidative burst in the MCD model. Innovation and Conclusions: Gliptins via suppression of inflammation decrease steatosis, apoptosis, oxidative stress, and vascular dysfunction in murine models of NASH and liver fibrosis, with mild direct antifibrotic properties. They reduce the numbers of liver and vascular inflammatory monocytes/macrophages and induce their alternative polarization, with beneficial effect on NASH-associated hepatic and cardiovascular complications. Therefore, gliptins qualify as drugs for treatment of NASH and associated liver fibrosis and cardiovascular complications. Antioxid. Redox Signal. 28, 87-109.
非酒精性脂肪性肝炎（NASH）的特征为脂肪变性、全小叶炎症、肝纤维化和心血管死亡率增加。二肽基肽酶-4 抑制剂（gliptins）是间接胰高血糖素样肽 1 激动剂，具有抗糖尿病和抗炎活性，用于治疗 2 型糖尿病。它们在治疗代谢性肝炎症和纤维化以及相关血管功能障碍方面的潜在作用和潜在机制仍有待探索。
在 NASH 和肝纤维化的蛋氨酸/胆碱缺乏（MCD）饮食和 Mdr2 模型中，西格列汀和利拉利汀的治疗显著降低了脂肪变性和炎症的参数，同时伴随着代谢性炎症和纤维化的肝转录水平的抑制，包括 SREBP-1c、FAS、TNFα、iNOS、α-SMA、Col1α1 和 MMP-12。此外，gliptins 减少了肝浸润的 CD11bLy6C 促炎单核细胞/巨噬细胞和肝驻留的 F4/80 巨噬细胞的数量，增加了 Ym1 替代巨噬细胞和（抗炎）巨噬细胞标记物 Arg1 和 IL-10。这与肝和主动脉活性氧（ROS）产生和 NOX-2mRNA 表达的减少、内皮功能障碍的正常化、心脏 NADPH 氧化酶活性、线粒体 ROS 形成以及 MCD 模型中的全血氧化爆发相平行。
gliptins 通过抑制炎症减少了 NASH 和肝纤维化的小鼠模型中的脂肪变性、细胞凋亡、氧化应激和血管功能障碍，具有轻微的直接抗纤维化特性。它们减少了肝和血管炎症单核细胞/巨噬细胞的数量，并诱导其替代极化，对 NASH 相关的肝和心血管并发症有有益的影响。因此，gliptins 有资格成为治疗 NASH 和相关肝纤维化和心血管并发症的药物。
抗氧化。氧化还原信号。28,87-109。
