Defective fatty acid oxidation (FAO) has been implicated in diabetic kidney disease (DKD), yet little is known about the role of carnitine palmitoyltransferase-1A (CPT1A), a pivotal rate-limiting enzyme of FAO, in the progression of DKD. Here, we investigate whether CPT1A is a reliable therapeutic target for DKD. We first confirmed the downregulation expression of CPT1A in glomeruli from diabetic patients. We further evaluated the function of CPT1A in diabetic models. Overexpression of CPT1A exhibited protective effects in diabetic conditions, improving albuminuria and glomerular sclerosis, as well as mitigating glomerular lipid deposits and podocyte injury in streptozotocin-induced diabetic mice. Mechanistically, CPT1A not only fostered lipid consumption via fatty acid metabolism pathways, thereby reducing lipotoxicity, but also anchored Bcl2 to the mitochondrial membrane, thence preventing cytochrome C release and inhibiting the mitochondrial apoptotic process. Furthermore, a novel transcription factor of CPT1A, FOXA1, was identified. We elucidate the crucial role of CPT1A in mitigating podocyte injury and the progression of DKD, indicating that targeting CPT1A may be a promising avenue for DKD treatment.

中文翻译：

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CPT1A 在体外保护足细胞免受脂毒性和细胞凋亡，并在体内减轻糖尿病肾病

脂肪酸氧化缺陷（FAO）与糖尿病肾病（DKD）有关，但人们对肉碱棕榈酰转移酶-1A（CPT1A）（FAO 的关键限速酶）在 DKD 进展中的作用知之甚少。在这里，我们研究 CPT1A 是否是 DKD 的可靠治疗靶点。我们首先证实了糖尿病患者肾小球中 CPT1A 的表达下调。我们进一步评估了 CPT1A 在糖尿病模型中的功能。 CPT1A 的过度表达在糖尿病状况下表现出保护作用，改善蛋白尿和肾小球硬化，并减轻链脲佐菌素诱导的糖尿病小鼠的肾小球脂质沉积和足细胞损伤。从机制上讲，CPT1A不仅通过脂肪酸代谢途径促进脂质消耗，从而降低脂毒性，而且还将Bcl2锚定在线粒体膜上，从而阻止细胞色素C释放并抑制线粒体凋亡过程。此外，还鉴定出了 CPT1A 的一种新转录因子 FOXA1。我们阐明了 CPT1A 在减轻足细胞损伤和 DKD 进展中的关键作用，表明靶向 CPT1A 可能是 DKD 治疗的一个有前景的途径。