Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Nat Commun. 2023 Dec 21;14(1):8428. doi: 10.1038/s41467-023-44088-z.
Hepatic insulin resistance is central to the metabolic syndrome. Here we investigate the role of BTB and CNC homology 1 (BACH1) in hepatic insulin signaling. BACH1 is elevated in the hepatocytes of individuals with obesity and patients with non-alcoholic fatty liver disease (NAFLD). Hepatocyte-specific Bach1 deletion in male mice on a high-fat diet (HFD) ameliorates hyperglycemia and insulin resistance, improves glucose homeostasis, and protects against steatosis, whereas hepatic overexpression of Bach1 in male mice leads to the opposite phenotype. BACH1 directly interacts with the protein-tyrosine phosphatase 1B (PTP1B) and the insulin receptor β (IR-β), and loss of BACH1 reduces the interaction between PTP1B and IR-β upon insulin stimulation and enhances insulin signaling in hepatocytes. Inhibition of PTP1B significantly attenuates BACH1-mediated suppression of insulin signaling in HFD-fed male mice. Hepatic BACH1 knockdown ameliorates hyperglycemia and improves insulin sensitivity in diabetic male mice. These results demonstrate a critical function for hepatic BACH1 in the regulation of insulin signaling and glucose homeostasis.
肝脏胰岛素抵抗是代谢综合征的核心。在这里，我们研究了 BTB 和 CNC 同源性 1 (BACH1) 在肝脏胰岛素信号中的作用。肥胖个体和非酒精性脂肪性肝病 (NAFLD) 患者的肝细胞中 BACH1 水平升高。高脂饮食 (HFD) 喂养的雄性小鼠中肝细胞特异性 Bach1 缺失可改善高血糖和胰岛素抵抗，改善葡萄糖稳态，并防止脂肪变性，而在雄性小鼠中肝过度表达 Bach1 则导致相反的表型。BACH1 可直接与蛋白酪氨酸磷酸酶 1B (PTP1B) 和胰岛素受体 β (IR-β) 相互作用，而 Bach1 的缺失可减少胰岛素刺激时 PTP1B 和 IR-β 之间的相互作用，并增强肝细胞中的胰岛素信号。PTP1B 的抑制可显著减弱 HFD 喂养雄性小鼠中 BACH1 介导的胰岛素信号抑制。肝 Bach1 敲低可改善糖尿病雄性小鼠的高血糖并提高胰岛素敏感性。这些结果表明肝脏 Bach1 在调节胰岛素信号和葡萄糖稳态方面具有关键作用。
