GSTK1 alleviates ectopic fat deposition as a protective mechanism against diabetic renal tubulointerstitial lesions

  • Life Sci. 2026 Jul 15:397:124421. doi: 10.1016/j.lfs.2026.124421.
Hong Chen  1 ,  Yan Liu  2 ,  Ming-Ge Zhao  3 ,  Xue-Qin Wu  4 ,  Ai-Ming Dai  5 ,  Yu Wang  6 ,  Ye-Yi Yang  7 ,  Ai-Mei Li  8 ,  Wei Zhang  9 ,  Jun-Pu Wang  10 ,  Zhi-Jiao Zhou  11 ,  Ti-Chen  12 ,  Hao Zhang  13 ,  Shikun Yang  14
Affiliations
  • 1. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China; Department of Nephrology, Shaoyang Central Hospital, China. Electronic address: [email protected].
  • 2. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
  • 3. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
  • 4. Department of Nephrology, Shaoyang Central Hospital, China. Electronic address: [email protected].
  • 5. Department of Nephrology, Shaoyang Central Hospital, China. Electronic address: [email protected].
  • 6. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
  • 7. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
  • 8. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
  • 9. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
  • 10. Department of Electron Microscope Analysis Center, Xiangya Hospital, Central South University, China. Electronic address: [email protected].
  • 11. Department of Pathology, The Third Xiangya Hospital, Central South University, China. Electronic address: [email protected].
  • 12. Department of Clinical laboratory, The Third Xiangya Hospital, Central South University, China. Electronic address: [email protected].
  • 13. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
  • 14. Department of Nephrology, The Third Xiangya Hospital, The Critical Kidney Disease Research Center, Central South University, China. Electronic address: [email protected].
PMID: 42069296 DOI: 10.1016/j.lfs.2026.124421
Abstract

Aims: The kappa class of glutathione S-transferases 1 (GSTK1) is a vital regulatory factor in metabolic diseases. This study was conducted to investigate the regulatory effects of GSTK1 on renal ectopic fat deposition (EFD) and lipotoxic injury in diabetic nephropathy (DN) .

Results: HK-2 cells under high glucose(HG) / high fatty acid (HFA) stimulation, diabetic mice and human renal biopsy tissues were used. GSTK1 plasmid, GSTK1 siRNA and OSBPL8 siRNA were applied in vitro. Lipid accumulation was analyzed in the renal tissue of type 2 DN patients, diabetic mice and HK-2 cells under HG/HFA stimulation. The expression of GSTK1, DGAT1, ACAT1, CPT-1, Beclin1, LC3II, ATG5 and RAB7 in renal tubular cells of diabetic mice and HK-2 cells under HG/HFA condition decreased significantly. Metformin treatment restored the expression of GSTK1 in diabetic mice. Additionally, the GSTK1 pharmacological modulator metformin relieved lipophagy dysfunction and promoted fatty acid (FA) β-oxidation enzyme CPT-1. In vitro, GSTK1 plasmid reduced lipid accumulation, fibrosis and inflammation and up-regulated the expression of CPT1 in HK-2 cells, but GSTK1 plasmid had no effect on lipid metabolizing Enzymes (ACAT1, DGAT1) . In addition, GSTK1 plasmid could obviously restore lipophagy. However, pretreatment of HK-2 cells with the AMPK Inhibitor Compound C, GSTK1 siRNA or OSBPL8 siRNA negated the activating effects of GSTK1 on lipophagy.

Conclusion: This study indicated that GSTK1 could contribute to alleviate EFD in DN tubular cell through increasing the expression of FA β-oxidation enzyme CPT-1 and restoring lipophagy via AMPK-OSBPL8 pathway.

Keywords
DN; EFD; Fatty acid beta oxidation; GSTK1; Lipophagy; Renal tubular cell.
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