ATP-柠檬酸裂解酶抑制剂改善 db/db 小鼠模型肾脏中的异位脂质积累,Frontiers in Endocrinology

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ATP-柠檬酸裂解酶抑制剂改善 db/db 小鼠模型肾脏中的异位脂质积累
Frontiers in Endocrinology ( IF 3.9 ) Pub Date : 2022-12-08 , DOI: 10.3389/fendo.2022.914865
Zishun Zhan _{1,

2} , Aimei Li _{1,

2} , Wei Zhang _{1,

2} , Xueqin Wu _{1,

2} , Jinrong He _{1,

2} , Zhi Li _{1,

2} , Yanchun Li ₃ , Jian Sun _{1,

2,

4} , Hao Zhang _{1,

2}

Affiliation

目的我们评估了一种治疗肥胖相关肾脏疾病的新疗法，一种 ATP 柠檬酸裂解酶 (ACL) 抑制剂，可减轻肾脏异位脂质积累 (ELA) 和随之而来的炎症。材料和方法将 ACL 抑制剂胃内给药至 12 周-旧的 db/db 小鼠 30 天。通过用油红O染色肾切片观察ELA的出现，并通过质谱评估组织脂质代谢物的差异。通过组织学检查和多种生化分析观察了 ACL 抑制剂的抗肥胖和肾脏保护作用。结果使用 AutoDock Vina 应用程序，我们确定了四种已知的 ACL 抑制剂（SB-204990、ETC-1002、NDI-091143 和 BMS） -303141)，BMS-303141 对 ACL 具有最高的亲和力，并降低了 db/db 小鼠肾脏中的 ACL 表达。我们报告说，BMS-303141 给药可以降低 db/db 小鼠的血清脂质和肾脂肪生成酶乙酰辅酶 A 羧化酶 (ACC)、脂肪酸合酶 (FAS)、HMG-CoA 还原酶 (HMGCR) 的水平，并减少肾 ELA . 此外，我们发现减少 ELA 可改善肾损伤、炎症和肾小管间质纤维化。结论 ACL 抑制剂 BMS-303141 可防止肥胖相关的肾损伤。

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ATP-citrate lyase inhibitor improves ectopic lipid accumulation in the kidney in a db/db mouse model

AimWe evaluated a novel treatment for obesity-related renal, an ATP-citrate lyase (ACL) inhibitor, to attenuate ectopic lipid accumulation (ELA) in the kidney and the ensuing inflammation.Materials and methodsAn ACL inhibitor was administered intragastrically to 12-week-old db/db mice for 30 days. The appearance of ELA was observed by staining kidney sections with Oil Red O, and the differences in tissue lipid metabolites were assessed by mass spectrometry. The anti-obesity and renoprotection effects of ACL inhibitors were observed by histological examination and multiple biochemical assays.ResultsUsing the AutoDock Vina application, we determined that among the four known ACL inhibitors (SB-204990, ETC-1002, NDI-091143, and BMS-303141), BMS-303141 had the highest affinity for ACL and reduced ACL expression in the kidneys of db/db mice. We reported that BMS-303141 administration could decrease the levels of serum lipid and renal lipogenic enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), HMG-CoA reductase (HMGCR), and diminish renal ELA in db/db mice. In addition, we found that reducing ELA improved renal injuries, inflammation, and tubulointerstitial fibrosis.ConclusionACL inhibitor BMS-303141 protects against obesity-related renal injuries.

更新日期：2022-12-08

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