BACH1 controls hepatic insulin signaling and glucose homeostasis in mice

• Published in: Nature communications 2023-12, Vol.14 (1), p.8428-8428, Article 8428
• Main Authors: Jin, Jiayu, He, Yunquan, Guo, Jieyu, Pan, Qi, Wei, Xiangxiang, Xu, Chen, Qi, Zhiyuan, Li, Qinhan, Ma, Siyu, Lin, Jiayi, Jiang, Nan, Ma, Jinghua, Wang, Xinhong, Jiang, Lindi, Ding, Qiurong, Osto, Elena, Zhi, Xiuling, Meng, Dan
• Format: Article
• Language: English
• Subjects: 13/1; 13/95; 14; 14/1; 38; 38/1; 38/35; 38/5; 38/77; 38/79; 631/80/304; 692/308/1426; Diabetes; Diabetes mellitus; Diet; Fatty liver; Glucose; Hepatocytes; High fat diet; Homeostasis; Homology; Humanities and Social Sciences; Hyperglycemia; Insulin; Insulin resistance; Liver diseases; Males; Metabolic disorders; Metabolic syndrome; multidisciplinary; Phenotypes; Protein-tyrosine phosphatase 1B; Protein-tyrosine-phosphatase; Science; Science (multidisciplinary); Steatosis; Tyrosine
• ISSN: 2041-1723; 2041-1723
• 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. Hepatic insulin resistance plays a central role in metabolic syndrome. Here, the authors show that transcription factor BACH1 acts as a negative regulator of insulin signaling and that hepatic BACH1 deficiency ameliorates hyperglycemia and insulin resistance in high-fat diet-fed or diabetic mice