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Abstract: TH-PO612

GCN5-Like Protein 1 Controls Lipotoxicity in Proximal Tubule Cells by Regulating Fatty Acid Oxidation via Mitochondrial Enzyme Acetylation

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic


  • Xin, Wei, Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
  • Lv, Tingting, Shandong Provincial Qianfoshan Hospital affiliated to Shandong University, Jinan, China
  • Hu, Yanyan, Tai'an City Central Hospital, Tai'an, China
  • Sun, Hongjun, Shandong Provincial Qianfoshan Hospital affiliated to Shandong University, Jinan, China
  • Wan, Qiang, Shandong Provincial Qianfoshan Hospital affiliated to Shandong University, Jinan, China

Lipotoxicity termed as the accumulation of satuarated nonesterified fatty acid (NEFA) and their metabolites playS a vital role during the progression of chronic kidney disease (CKD). NEFA catabolism is mainly through the b-oxidation in mitochondria. Due to a high energy demand and relatively little glycolytic capacity, fatty acid oxidation (FAO) is particularly important for the proximal tubule cells. However, the upstream mechanisms remain unclear. Lysine acetylation is a reversible post-translational modification, and is particularly important in the regulation of mitochondrial metabolic enzymes. However, the effects of acetylation status on the NEFA b-oxidation and lipotoxicity in the proximal tubule cells remains unclear. In this study, we aimed to investigate how FAO rate in the tubule cells is controlled by mitochondrial acetylation status and how these changes affect lipotoxicity.


Human proximal tubular epithelial cells (HK-2) were stimulated with palmitic acid (PA) and C57BL/6 mice were received a high-fat diet (HFD) for 18 weeks. The expression of acetylated-lysine and GCN5-like Protein 1 (GCN5L1) were detected by both immunohistochemistry and western blot. The immunoprecipitation assay was used to evaluate the acetylation levels of long-chain acyl-CoA dehydrogenases (LCAD) and 3-hydroxyacyl-CoA dehydrogenase (β-HAD). Fatty acid β-oxidation rate, triglyceride content, ac-CoA, and the activity of LCAD and β-HAD were assessed by appropriate kits.


The expression of total lysine acetylation was increased in palmictic acid (PA) cultured HK-2 cells and high-fat feeding mice kidneys. PA induced LCAD and β-HAD hyperacetylation and reduced enzymatic activity along with decreased fatty acid oxidation rate and ac-CoA contents. Interestingly, GCN5L1 was upregulated in vivo and vitro high fat conditions. Finally, the silence of GCN5L1 in HK-2 cells led to the deacetylation of LCAD and β-HAD and accelerated FAO rate, which eventually attenuated lipid deposition.


The acetylation of mitochondrial proteins supressed FAO in renal proximal tubule cells. GCN5L1 suppression attenuates lipotoxicity by upregulating FAO via reversible mitochondrial enzyme LCAD and β-HAD acetylation.The manipulation of acetylation status might act as a promising therapeutic intervention for lipotoxicity in CKD.


  • Government Support - Non-U.S.