Dyslipidemia is a common risk factor of chronic kidney disease (CKD). Current notion suggests that insufficient intracellular fatty acid oxidation (FAO) and subsequently enhanced fatty acid esterification within renal resident cells, a process termed as renal lipotoxicity, is the key pathogenic event responsible for dyslipidemia-induced kidney injury. However, the detailed mechanism is not fully elucidated. Recently, accumulating data indicated that acetylation modification is an important regulating manner for both mitochondrial function and energy metabolism, while whether acetylation modification is involved in renal lipotoxicity is of little known. In the present study, the expression level of global lysine acetylation was detected by immunohistochemistry in high-fat diet mice and western blot in palmitic acid (PA) stimulated HK-2 cells. The acetylation levels of long-chain acyl-CoA dehydrogenases (LCAD) and β-hydroxyacyl-CoA dehydrogenase (β-HAD) were measured by immunoprecipitation. And a multifunction microplate reader was applied to detect FAO rate, triglyceride and acyl-CoA contents, and the enzyme activities, with cellular lipid accumulation identified by Oil Red O staining. We evidenced the acetylation levels of LCAD and β-HAD that were enhanced, which led to decreased enzymatic activities and impaired FAO rate. Furthermore, renal protein hyperacetylation induced by lipid overload was associated with increased expression of GCN5L1. And the silence of GCN5L1 in tubular epithelial cells resulted in deacetylation and activation of LCAD and β-HAD. Finally, excess lipids induced lipotoxicity and epithelial-mesenchymal transition (EMT) were ameliorated by GCN5L1 suppression, suggesting GCN5L1-mediated mitochondrial LCAD and β-HAD acetylation might be a key pathogenic event underlying excess lipids induced FAO impairment.

中文翻译：

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GCN5L1通过调节脂肪酸氧化酶的乙酰化作用来控制肾毒性。

血脂异常是慢性肾脏病（CKD）的常见危险因素。目前的观念表明，细胞内脂肪酸氧化不足（FAO）和随后在肾驻留细胞内增强的脂肪酸酯化作用（称为肾脂毒性）是导致血脂异常诱导的肾损伤的关键病原性事件。但是，详细的机制尚未完全阐明。近来，积累的数据表明乙酰化修饰是线粒体功能和能量代谢的重要调节方式，而乙酰化修饰是否参与肾脏脂毒性尚不清楚。在本研究中，通过免疫组织化学在高脂饮食小鼠中检测整体赖氨酸乙酰化的表达水平，并在棕榈酸（PA）刺激的HK-2细胞中进行Western印迹检测。通过免疫沉淀法测定长链酰基辅酶A脱氢酶（LCAD）和β-羟酰基辅酶A脱氢酶（β-HAD）的乙酰化水平。并将多功能酶标仪用于检测FAO率，甘油三酸酯和酰基辅酶A含量以及酶活性，并通过油红O染色鉴定细胞脂质的积累。我们证明了LCAD和β-HAD的乙酰化水平提高了，这导致了酶活性的降低和FAO率的降低。此外，脂质超负荷诱导的肾蛋白过度乙酰化与GCN5L1表达增加有关。GCN5L1在肾小管上皮细胞中的沉默导致LCAD和β-HAD的脱乙酰化和活化。最后，通过抑制GCN5L1可以改善脂质过多引起的脂质毒性和上皮-间质转化（EMT），