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

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. Yao and Gong et al. identify WD40 repeat-containing protein 6 (WDR6) to be upregulated in the liver of insulin-resistant mice. WDR6 contributes to promoting hepatic de novo lipogenesis during insulin resistance by upregulation of fatty acid synthase, and the authors identify a small molecule to inhibit this effect of WDR6 and reduce hepatic steatosis.

Automated summary

In this study, it is shown that WDR6 promotes hepatic de novo lipogenesis during insulin resistance by interacting with PPP1CB. A small natural compound, XLIX, is also identified as an inhibitor of the WDR6-PPP1CB interaction, reducing hepatic steatosis in insulin resistance.