TLT-1，肥胖和非酒精性脂肪肝（NAFLD）炎症发病机制的潜在调节剂,Blood

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TLT-1，肥胖和非酒精性脂肪肝（NAFLD）炎症发病机制的潜在调节剂
Blood ( IF 21.0 ) Pub Date : 2021-11-05 , DOI: 10.1182/blood-2021-153403
Siobhan Laken Branfield ₁ , Benjamin Nieves Lopez ₂ , Matthew E Poynter ₃ , Anthony Valance Washington ₄

Affiliation

摘要背景：肥胖是一个全国性的健康问题，在美国每年的相关医疗费用在 147-2100 亿美元之间，并且与患 NAFLD 的风险增加 3.5 倍有关。在肥胖症中，血小板以多效性方式与血管和免疫细胞一起作用，以放大慢性炎症过程。有趣的是，研究表明肥胖个体的血小板数量和反应性增加。激活的血小板在肥胖引起的炎症中的新兴作用引入了血小板靶向治疗干预的新概念。Kopec 等人进一步支持了肥胖进展的机制在于血小板介导的促炎状态的观点，说明西方饮食小鼠的白色脂肪组织和肝脏内存在血管外纤维蛋白（原）沉积、巨噬细胞和炎性细胞因子。Kopec 等人使用缺乏 Mac-1 结合基序的纤维蛋白原突变小鼠 (Fiby390-396) 并抑制配体与白细胞的相互作用，减少炎症，减少巨噬细胞计数，减轻体重，保护小鼠免受 NAFLD 和葡萄糖代谢异常。总之，所有证据都指向了肥胖发展的潜在血小板/纤维蛋白原/白细胞病理生理机制。TREM-Like Transcript-1 (TLT-1) 是一种血小板特异性受体，存在于血小板的 a 颗粒中，并在血小板活化后释放到表面。TLT-1 是一种 1 型受体，与整合素 a2bb3 一样，结合纤维蛋白原并促进血小板聚集。然而，尽管 TLT-1 可能有助于凝块形成和止血以在非炎症/非免疫介导的环境中止血，但 TLT-1 的主要关联是调节炎症性出血。与对照组相比，treml1 -/- 小鼠在炎症治疗（如脂多糖 LPS）后出血增加证明了这一点。考虑到支持血小板-纤维蛋白原受体配体相互作用作为肥胖发展的关键机制的新证据，以及血小板特异性受体 TLT-1 结合纤维蛋白原并介导白细胞运输，我们的实验室着手确定 TLT-1可能被认为是这种机制背后的罪魁祸首。当采用西方饮食时，treml1 -/-小鼠更容易体重增加，基于这些发现，我们假设：TLT-1/纤维蛋白原分子相互作用调节肥胖中的代谢炎症目标：评估西方饮食对 treml1 中肥胖和 NAFLD 的影响 -/ - 小鼠模型方法：TLT-1 (treml1 -/-) - 载脂蛋白 E (apoe -/-) 双空 (AT-DKO;n=11) 小鼠和对照 apoe +/-/treml1 +/- littermate 对照 (AT -Hets；n=20) 喂食西方饮食 20 周。收集血浆样本用于脂肪因子、葡萄糖、胰岛素、肝酶和脂质分析。对小鼠进行灌注，收集肝脏和脂肪组织用于组织学分析。结果：总体而言，AT-DKO 小鼠与 AT-Hets 相比体重增加更多（12.94±1.90 对 8.51±1.70 克 p=0.02）。血浆分析表明，AT-DKO 具有更高水平的 TNF-a（0.54±0.60 vs 0.118±0.17 pg/ml p=0.03）和 IL-10（2.50±1.40 vs 1.50±2.10 pg/ml p=0.004）与同窝对照相比。肝脏的组织学分析表明，与对照组相比，AT-DKO 小鼠的脂质空泡和炎症灶增加，虽然初步数据对于这些差异并不显着，但 AT-DKO 中的肝损伤显着更大，如 AST 水平增加所示 (166.21 ±91.00 与 102±68.10 U/L p=0.02)。此外，AT-DKO 小鼠具有较高水平的 ALT、直接胆红素、胆固醇、pai-1、甘油三酯和较低的 IL-6 和脂联素（表 1 数据不显着）。这些发现表明，在没有 TLT-1 的情况下，这些小鼠更容易出现肝功能障碍、高脂血症和炎症改变。结论：与同窝对照相比，突变的 AT-DKO 小鼠更容易发生肥胖和 NAFLD，这表明血小板基因 TLT-1 在新陈代谢中起着令人惊讶的作用。进一步的研究可以判定 TLT-1 给药是预防和改善肥胖及相关病理的潜在治疗干预。该项目的当前状态将在此处报告。图 1 图 1. 披露无需声明相关的利益冲突。进一步的研究可以判定 TLT-1 给药是预防和改善肥胖及相关病理的潜在治疗干预。该项目的当前状态将在此处报告。图 1 图 1. 披露无需声明相关的利益冲突。进一步的研究可以判定 TLT-1 给药是预防和改善肥胖及相关病理的潜在治疗干预。该项目的当前状态将在此处报告。图 1 图 1. 披露无需声明相关的利益冲突。

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TLT-1, a Potential Regulator of Inflammatory Pathogenesis in Obesity and Non-Alcoholic Fatty Liver Disease (NAFLD)

Abstract Background: Obesity, a nationwide health issue, has related medical costs ranging between $147-210 billion per year in United States and has been associated with a 3.5-fold increased risk of developing NAFLD. In obesity, platelets work in a pleotropic manner with vascular and immune cells to amplify the chronic inflammatory process. Interestingly, studies have demonstrated that platelet numbers and reactivity are increased in obese individuals. The emerging role of activated platelets during obesity induced inflammation introduces the novel concept of platelet targeted therapeutic interventions. Kopec et al, further supports the idea that the mechanism underlying the progression of obesity lies in a platelet mediated pro-inflammatory state, illustrating that there is extravascular fibrin(ogen) deposition, macrophages and inflammatory cytokines within white adipose tissue and liver of mice on western diet. Kopec et al uses a fibrinogen mutant mouse (Fiby390-396 ) which lacks the binding motif for Mac-1 and inhibits the ligand interaction with leukocytes, diminishing inflammation, reducing macrophage counts, reducing weight, protects mice from NAFLD and glucose dysmetabolism. Taken together, all evidence points towards a platelet/fibrinogen/leukocyte pathophysiological mechanism underlying the development of obesity. TREM-Like Transcript-1 (TLT-1) is a platelet specific receptor found in the a-granules of platelets and released to the surface upon platelet activation. TLT-1 is a type 1 receptor that, like the integrin a2bb3, binds fibrinogen and facilitates platelet aggregation . However, although TLT-1 may assist in clot formation and hemostasis to arrest bleeding in a non-inflammatory/nonimmune mediated setting, TLT-1's main association is with regulating inflammatory-derived bleeding. This is demonstrated by increased hemorrhage after inflammatory treatments such as lipopolysaccharide LPS in the treml1 -/- mice as compared to controls. Considering the emerging evidence in support of a platelet-fibrinogen receptor ligand interaction as a key mechanism underlying the development of obesity and that TLT-1, a platelet specific receptor binds fibrinogen and mediates leukocyte trafficking, our laboratory set out to determine whether TLT-1 could be implicated as the main culprit underlying this mechanism. When placed on a western diet, treml1 -/-mice are more prone to weight gain, based on these finding we hypothesize that: The TLT-1/Fibrinogen molecular interaction regulates metabolic inflammation in obesity Aims: Evaluate the effects of western diet on obesity and NAFLD in the treml1 -/- mouse model Methods: TLT-1 (treml1 -/-) - apolipoprotein E (apoe -/-) double null (AT-DKO;n=11) mice and control apoe +/-/treml1 +/- littermate controls (AT-Hets;n=20) were fed western diet for 20 weeks. Plasma samples were collected for adipokine, glucose, insulin, liver enzyme and lipid profiling. Mouse were perfused, liver and adipose tissue were collected for histological analysis. Results: Overall AT-DKO mice gained more weight compared to AT-Hets (12.94±1.90 vs 8.51±1.70 grams p=0.02). Plasma analysis demonstrates that the AT-DKO have higher levels of TNF-a (0.54±0.60 vs 0.118±0.17 pg/ml p=0.03), and IL-10 (2.50±1.40 vs 1.50±2.10 pg/ml p=0.004) compared to littermate controls. Histological analysis of livers illustrates increased lipid vacuoles and inflammatory foci in the AT-DKO mice as compared to controls, while preliminary data is not significant for these differences, liver damage in the AT-DKO was significantly greater as demonstrated by increased AST levels (166.21±91.00 vs 102±68.10 U/L p=0.02). Moreover, the AT-DKO mice had higher levels of ALT, direct bilirubin, cholesterol, pai-1 , triglycerides and lower IL-6 and Adiponectin (Table 1 data not significant). These findings suggest that in the absence of TLT-1 these mice are more prone to liver disfunction , hyperlipidemia and inflammatory alterations. Conclusions: Mutant AT-DKO mice are more prone to obesity and NAFLD compared to littermate controls, suggesting that TLT-1, a platelet gene, plays a surprising role in metabolism. Further investigation could adjudicate TLT-1 administration as a potential therapeutic intervention for prevention and amelioration of Obesity and related pathologies. The current state of this project will be reported here. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

更新日期：2021-11-05

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