Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
Hubei Key Laboratory of Digestive System Disease, Wuhan, Hubei, China.
Oxid Med Cell Longev. 2020 Jan 8;2020:8172714. doi: 10.1155/2020/8172714. eCollection 2020.
High-fat diet (HFD) often increases oxidative stress and enhances inflammatory status in the body. Toll-like receptor 4 (TLR4) is widely expressed in the pancreatic tissues and plays an important role in pancreatitis. This study is aimed at investigating the effect of HFD on acute pancreatitis (AP) and the role of TLR4-mediated necroptosis and inflammation in this disease. Weight-matched rats were allocated for an 8-week feeding on the standard chow diet (SCD) or HFD, and then, the AP model was induced by infusion of 5% sodium taurocholate into the biliopancreatic duct. Rats were sacrificed at an indicated time point after modeling. Additionally, inhibition of TLR4 signaling by TAK-242 in HFD rats with AP was conducted The results showed that the levels of serum free fatty acid (FFA) in HFD rats were higher than those in SCD rats. Moreover, HFD rats were more vulnerable to AP injury than SCD rats, as indicated by more serious pathological damage and much higher pancreatic malondialdehyde (MDA) and lipid peroxidation (LPO) levels as well as lower pancreatic superoxide dismutase (SOD) activities and reduced glutathione (GSH) contents and more intense infiltration of MPO-positive neutrophils and CD68-positive macrophages. In addition, HFD markedly increased the expressions of TLR4 and necroptosis marker (RIP3) and aggravated the activation of NF-B p65 and the expression of TNF- in the pancreas of AP rats at indicated time points. However, TLR4 inhibition significantly attenuated the structural and functional damage of the pancreas induced by AP in HFD rats, as indicated by improvement of the above indexes. Taken together, these findings suggest that HFD exacerbated the extent and severity of AP oxidative stress, inflammatory response, and necroptosis. Inhibition of TLR4 signaling by TAK-242 alleviated oxidative stress and decreased inflammatory reaction and necroptosis, exerting a protective effect during AP in HFD rats.
高脂肪饮食（HFD）通常会增加体内的氧化应激并增强炎症状态。Toll 样受体 4（TLR4）广泛表达于胰腺组织中，在胰腺炎中发挥重要作用。本研究旨在探讨 HFD 对急性胰腺炎（AP）的影响，以及 TLR4 介导的坏死性凋亡和炎症在该疾病中的作用。将体重匹配的大鼠分为 8 周标准饲料（SCD）或 HFD 喂养组，然后通过向胆胰管输注 5%牛磺胆酸钠诱导 AP 模型。建模后在指定时间点处死大鼠。此外，还在 HFD 伴 AP 大鼠中通过 TAK-242 抑制 TLR4 信号。结果表明，HFD 大鼠血清游离脂肪酸（FFA）水平高于 SCD 大鼠。此外，与 SCD 大鼠相比，HFD 大鼠对 AP 损伤更敏感，表现为更严重的病理损伤，胰腺丙二醛（MDA）和脂质过氧化（LPO）水平更高，胰腺超氧化物歧化酶（SOD）活性和还原型谷胱甘肽（GSH）含量更低，MPO 阳性中性粒细胞和 CD68 阳性巨噬细胞浸润更强烈。此外，HFD 明显增加了 TLR4 和坏死性凋亡标志物（RIP3）的表达，并在各时间点加重了 NF-B p65 的激活和 TNF-α在 AP 大鼠胰腺中的表达。然而，TLR4 抑制显著减轻了 HFD 大鼠 AP 引起的胰腺结构和功能损伤，上述指标得到改善。总之，这些发现表明 HFD 加重了 AP 时的氧化应激、炎症反应和坏死性凋亡的程度和严重程度。TAK-242 抑制 TLR4 信号可减轻氧化应激，减少炎症反应和坏死性凋亡，在 HFD 大鼠 AP 中发挥保护作用。
