Research Paper Volume 14, Issue 21 pp 8763—8782
HBP1 inhibits the development of type 2 diabetes mellitus through transcriptional activation of the IGFBP1 gene
- 1 Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Peking University Health Science Center, Beijing 100191, P. R. China
Received: June 9, 2022 Accepted: October 21, 2022 Published: November 2, 2022
https://doi.org/10.18632/aging.204364How to Cite
Copyright: © 2022 Cheng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease that is highly prevalent worldwide and characterized by glucose and lipid metabolism disorders. However, the pathogenic mechanisms have not been fully established. Here, we found that HMG-box transcription factor 1 (HBP1) is involved in T2DM and that its deficiency in mice aggravates the features of diabetes. In addition, we undertook screening by RNA sequencing and found that HBP1 activates the transcription of the insulin-like growth factor binding protein 1 (IGFBP1) gene. Moreover, Insulin and palmitic acid reduced HBP1 protein expression and inhibited its binding to the IGFBP1 promoter. Furthermore, HBP1 reduced the serum free insulin-like growth factor 1 (IGF-1) concentration through IGFBP1 and inhibited the PI3K/AKT signaling pathway. This forms an insulin/HBP1/IGFBP1 negative feedback regulatory loop to dynamically regulate blood glucose and insulin concentrations. These findings have elucidated a mechanism whereby HBP1 and its negative feedback regulatory loop influence the development of T2DM, thereby providing a new theoretical basis and potential therapeutic target for T2DM.
Abbreviations
HBP1: High mobility group (HMG) box-containing protein 1; IGFBP1: insulin-like growth factor binding protein 1; T2DM: type 2 diabetes mellitus; PI3K: phosphoinositide 3-kinase; AKT: protein kinase B; IGF-1: insulin-like growth factor-1; IGF-1R: IGF-1 receptor; IRE: insulin response element; NAFLD: nonalcoholic fatty liver disease; ND: normal diet; HFD: high fat diet; WT: wild type; OGTT: oral glucose tolerance testing; ITT: insulin tolerance testing; PTT: pyruvate tolerance testing; KEGG: Kyoto Encyclopedia of Genes and Genomes; shRNA: short hairpin RNA; ChIP: chromatin immunoprecipitation; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; DMEM: Dulbecco’s modified eagle medium; EBSS: Earle's Balanced Salt Solution; ELISA: enzyme linked immunosorbent assay; PA: palmitic acid.