Institute of Health Sciences, China Medical University, Shenyang, 110122, China.
Department of Chemistry, School of Fundamental Sciences, China Medical University, Shenyang, 110122, China.
Inflammation. 2020 Oct;43(5):1884-1892. doi: 10.1007/s10753-020-01261-6.
Although obesity is associated with inflammatory bowel disease (IBD), the underlying molecular mechanism still remains unclear. In this study, we evaluated the effects of high-fat diet (HFD)-induced obesity on the development of experimental colitis in mice. The C57BL/6 mice were fed with a HFD for 12 weeks to develop obesity. The concentrations of free fatty acids (FFA), triglycerides, and cholesterol in plasma were significantly increased in HFD-fed mice compared to low-fat diet (LFD)-fed mice. We found that HFD-induced obesity could exacerbate 2,4,6-trinitro-benzene-sulfonic acid (TNBS)-induced experimental colitis in mice resembling Crohn's disease (CD). HFD-fed mice showed shorter colon length, higher clinical scores and histological scores, more production of mucosal tumor necrosis factor-α (TNF-α), and greater destruction of colonic epithelial barrier than LFD-fed mice after TNBS induction. HFD feeding also promoted reactive oxygen species (ROS) production in colonic epithelial cells, thus activating the pro-apoptotic pathway to damage colonic epithelial barrier induced by TNBS. After HCT116 cells were treated with palmitate acid (PA) and/or TNF-α for 24 h, the combination of PA and TNF-α increased ROS production, promoted mitochondrial dysfunction, and activated the pro-apoptotic pathway, but these effects were markedly attenuated by a ROS inhibitor. Taken together, these observations suggest that HFD-induced obesity promotes experimental colitis by increasing oxidative stress and mitochondrial dysfunction, which triggers the activation of pro-apoptotic pathway in the colon.
虽然肥胖与炎症性肠病（IBD）有关，但潜在的分子机制仍不清楚。在这项研究中，我们评估了高脂肪饮食（HFD）诱导的肥胖对小鼠实验性结肠炎发展的影响。C57BL/6 小鼠用 HFD 喂养 12 周以发展肥胖。与低脂饮食（LFD）喂养的小鼠相比，HFD 喂养的小鼠血浆中游离脂肪酸（FFA）、甘油三酯和胆固醇的浓度显著增加。我们发现 HFD 诱导的肥胖可加重 2,4,6-三硝基苯磺酸（TNBS）诱导的类似于克罗恩病（CD）的小鼠实验性结肠炎。与 LFD 喂养的小鼠相比，HFD 喂养的小鼠在 TNBS 诱导后具有更短的结肠长度、更高的临床评分和组织学评分、更多的粘膜肿瘤坏死因子-α（TNF-α）产生和更严重的结肠上皮屏障破坏。HFD 喂养还促进了结肠上皮细胞中活性氧（ROS）的产生，从而激活了 TNBS 诱导的结肠上皮屏障损伤的促凋亡途径。在 HCT116 细胞用棕榈酸（PA）和/或 TNF-α处理 24 小时后，PA 和 TNF-α 的组合增加了 ROS 的产生，促进了线粒体功能障碍，并激活了促凋亡途径，但这些作用被 ROS 抑制剂显著减弱。总之，这些观察结果表明，HFD 诱导的肥胖通过增加氧化应激和线粒体功能障碍来促进实验性结肠炎，从而触发结肠中促凋亡途径的激活。
