Upregulation of WDR6 Drives Hepatic de novo Lipogenesis in Insulin Resistance

Under normal conditions, insulin promotes hepatic de novo lipogenesis (DNL). However, during insulin resistance (IR), when insulin signaling is blunted and accompanied by hyperinsulinemia, 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.正常生理状态下，胰岛素可促进肝脏内的从头脂肪生成（hepatic de novo lipogenesis, DNL）。然而，在胰岛素抵抗（insulin resistance, IR）状态下，当胰岛素信号通路受阻且伴随高胰岛素血症时，肝脏从头脂肪生成的促进作用仍未减弱，进而导致肝脏脂肪变性加重。本研究发现，含WD40重复序列的蛋白6（WD40-repeat containing protein 6, WDR6）可在胰岛素抵抗状态下促进肝脏从头脂肪生成。机制层面，WDR6可与丝氨酸/苏氨酸蛋白磷酸酶1的β型催化亚基（serine/threonine-protein phosphatase 1 beta-type catalytic subunit, PPP1CB）相互作用，促进PPP1CB在Thr316位点的去磷酸化，随后通过DNA依赖蛋白激酶及上游刺激因子1增强脂肪酸合酶的转录。借助分子动力学模拟分析，本研究筛选得到一种天然小分子化合物XLIX，其可抑制WDR6与PPP1CB的相互作用，从而降低胰岛素抵抗状态下的肝脏从头脂肪生成。综上，本研究揭示WDR6可作为治疗肝脏脂肪变性的潜在靶点。