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GCN5L1 controls renal lipotoxicity through regulating acetylation of fatty acid oxidation enzymes

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Abstract

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.

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Funding

This work was supported by the National Natural Science Foundation of China (Grants No. 81570654, 31600699, 81770729, 91749111, and 81471007) and Shandong Province Taishan Scholar Project (Grants No.tsqn 20161073).

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Correspondence to Wei Xin or Qiang Wan.

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All animal experiments were carried out strictly according to the guidelines of the Animal Center of Shandong University, and the experimental procedures were approved by the Ethical Committee of Shandong Provincial Hospital affiliated to Shandong University (No. S077).

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Lv, T., Hu, Y., Ma, Y. et al. GCN5L1 controls renal lipotoxicity through regulating acetylation of fatty acid oxidation enzymes. J Physiol Biochem 75, 597–606 (2019). https://doi.org/10.1007/s13105-019-00711-6

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  • DOI: https://doi.org/10.1007/s13105-019-00711-6

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