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SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice

Abstract

Suppression of excessive hepatic gluconeogenesis is an effective strategy for controlling hyperglycemia in type 2 diabetes (T2D). In the present study, we screened our compounds library to discover the active molecules inhibiting gluconeogenesis in primary mouse hepatocytes. We found that SL010110 (5-((4-allyl-2-methoxyphenoxy) methyl) furan-2-carboxylic acid) potently inhibited gluconeogenesis with 3 μM and 10 μM leading to a reduction of 45.5% and 67.5%, respectively. Moreover, SL010110 caused suppression of gluconeogenesis resulted from downregulating the protein level of phosphoenolpyruvate carboxykinase 1 (PEPCK1), but not from affecting the gene expressions of PEPCK, glucose-6-phosphatase, and fructose-1,6-bisphosphatase. Furthermore, SL010110 increased PEPCK1 acetylation, and promoted PEPCK1 ubiquitination and degradation. SL010110 activated p300 acetyltransferase activity in primary mouse hepatocytes. The enhanced PEPCK1 acetylation and suppressed gluconeogenesis caused by SL010110 were blocked by C646, a histone acetyltransferase p300 inhibitor, suggested that SL010110 inhibited gluconeogenesis by activating p300. SL010110 decreased NAD+/NADH ratio, inhibited SIRT2 activity, and further promoted p300 acetyltransferase activation and PEPCK1 acetylation. These effects were blocked by NMN, an NAD+ precursor, suggested that SL010110 inhibited gluconeogenesis by inhibiting SIRT2, activating p300, and subsequently promoting PEPCK1 acetylation. In type 2 diabetic ob/ob mice, single oral dose of SL010110 (100 mg/kg) suppressed gluconeogenesis accompanied by the suppressed hepatic SIRT2 activity, increased p300 activity, enhanced PEPCK1 acetylation and degradation. Chronic oral administration of SL010110 (15 or 50 mg/kg) significantly reduced the blood glucose levels in ob/ob and db/db mice. This study reveals that SL010110 is a lead compound with a distinct mechanism of suppressing gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and potent anti-hyperglycemic activity for the treatment of T2D.

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Fig. 1: SL010110 inhibits gluconeogenesis and decreases PEPCK1 protein levels in primary mouse hepatocytes.
Fig. 2: SL010110 suppresses gluconeogenesis by promoting PEPCK1 ubiquitination and degradation.
Fig. 3: SL010110 promotes PEPCK1 acetylation and indirectly increases p300 acetyltransferase activity.
Fig. 4: SL010110 inhibits gluconeogenesis through the activation of p300 acetyltransferase and the acetylation of PEPCK1.
Fig. 5: SL010110 inhibits cytoplasmic Sirt activity to promote p300 acetyltransferase activation and suppress gluconeogenesis.
Fig. 6: Sirtinol suppresses gluconeogenesis and increases PEPCK1 acetylation by activating p300 acetyltransferase.
Fig. 7: Acute treatment with SL010110 inhibits hepatic SIRT2 activity, increases p300 and PEPCK1 acetylation and suppresses gluconeogenesis in ob/ob mice.
Fig. 8: Pharmacokinetic changes of SL010110 in the serum and liver after administration to ob/ob mice by gavage.
Fig. 9: Chronic administration of SL010110 improves glucose homeostasis in diabetic ob/ob and db/db mice.

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Acknowledgements

This work was supported by grants from Science and Technology Commission of Shanghai Municipality (19431900900).

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Contributions

YL, JHS, and SLH designed the research. YRR, YLY, YF, TFX, YS, and JL performed the research. YRR, SLH, and YL analyzed and interpreted the data. YRR, SLH, and YL wrote the paper.

Corresponding authors

Correspondence to Su-ling Huang or Jian-hua Shen or Ying Leng.

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The authors declare no competing interests.

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Ren, Yr., Ye, Yl., Feng, Y. et al. SL010110, a lead compound, inhibits gluconeogenesis via SIRT2-p300-mediated PEPCK1 degradation and improves glucose homeostasis in diabetic mice. Acta Pharmacol Sin (2021). https://doi.org/10.1038/s41401-020-00609-w

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Keywords

  • SL010110
  • gluconeogenesis
  • primary mouse hepatocytes
  • PEPCK1
  • acetylation
  • degradation

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