BACH1 controls hepatic insulin signaling and glucose homeostasis in mice

Jiayu Jin, Yunquan He, Jieyu Guo, Qi Pan, Xiangxiang Wei, Chen Xu, Zhiyuan Qi, Qinhan Li, Siyu Ma, Jiayi Lin, Nan Jiang, Jinghua Ma, Xinhong Wang, Lindi Jiang, Qiurong Ding, Elena Osto, Xiuling Zhi () and Dan Meng ()
Additional contact information
Jiayu Jin: Fudan University
Yunquan He: Fudan University
Jieyu Guo: Fudan University
Qi Pan: Fudan University
Xiangxiang Wei: Fudan University
Chen Xu: Fudan University
Zhiyuan Qi: Fudan University
Qinhan Li: Fudan University
Siyu Ma: Fudan University
Jiayi Lin: Fudan University
Nan Jiang: Fudan University
Jinghua Ma: Fudan University
Xinhong Wang: Fudan University
Lindi Jiang: Fudan University
Qiurong Ding: University of Chinese Academy of Sciences, Chinese Academy of Sciences
Elena Osto: Medical University of Graz
Xiuling Zhi: Fudan University
Dan Meng: Fudan University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-44088-z

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