Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice

Zhenyu Yao, Ying Gong, Wenbin Chen, Shanshan Shao, Yongfeng Song, Honglin Guo, Qihang Li, Sijin Liu, Ximing Wang, Zhenhai Zhang, Qian Wang, Yunyun Xu, Yingjie Wu, Qiang Wan, Xinya Zhao, Qiuhui Xuan, Dawei Wang, Xiaoyan Lin, Jiawen Xu, Jun LiuChristopher G. Proud, Xuemin Wang, Rui Yang, Lili Fu, Shaona Niu, Junjie Kong, Ling Gao, Tao Bo, Jiajun Zhao

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signalling is blunted and accompanied by hyperinsulinaemia, the promotion of hepatic DNL continues unabated and hepatic steatosis increases. Here, we show that WD40 repeat-containing protein 6 (WDR6) promotes hepatic DNL during IR. Mechanistically, WDR6 interacts with the beta-type catalytic subunit of serine/threonine-protein phosphatase 1 (PPP1CB) to facilitate PPP1CB dephosphorylation at Thr316, which subsequently enhances fatty acid synthases transcription through DNA-dependent protein kinase and upstream stimulatory factor 1. Using molecular dynamics simulation analysis, we find a small natural compound, XLIX, that inhibits the interaction of WDR6 with PPP1CB, thus reducing DNL in IR states. Together, these results reveal WDR6 as a promising target for the treatment of hepatic steatosis.

Original languageEnglish
JournalNature Metabolism
DOIs
Publication statusPublished or Issued - 21 Sept 2023

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

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