Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, B-1070, Brussels, Belgium.
VIB-VUB Center for Structural Biology, Vlaams Instituut voor Biotechnologie, B-1050, Brussels, Belgium.
Nat Commun. 2024 Nov 4;15(1):9522. doi: 10.1038/s41467-024-53733-0.
Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.
脂肪积累、从头合成脂肪和糖酵解是肝细胞重编程和随后的代谢相关脂肪性肝病 (MASLD) 的关键驱动因素。在这里，我们报告肥胖导致肝蛋白酪氨酸磷酸酶 (PTP) 的表达失调。在人和小鼠的脂肪性肝细胞中发现 PTPRK 增加，并且与 PPARγ 诱导的脂肪生成信号呈正相关。高脂肪喂养的 PTPRK 敲除雄性和雌性小鼠体重增加减少，肝脂肪积累减少。在原代肝细胞和肝脏代谢组学中的磷酸蛋白质组学分析鉴定出果糖-1,6-二磷酸酶 1 和糖酵解是代谢重编程中 PTPRK 的靶标。在机制上，PTPRK 诱导的糖酵解增强了肝细胞中的 PPARγ 和脂肪生成。在肝癌细胞系中沉默 PTPRK 会降低集落形成能力，而高脂肪喂养的 PTPRK 敲除小鼠暴露于肝致癌物时会形成较小的肿瘤。我们的研究定义了 PTPRK 在肥胖症中调节肝糖酵解、脂质代谢和肿瘤发生中的作用。
