| First Author | Yong J | Year | 2021 |
| Journal | Sci Transl Med | Volume | 13 |
| Issue | 604 | PubMed ID | 34321322 |
| Mgi Jnum | J:322196 | Mgi Id | MGI:6752490 |
| Doi | 10.1126/scitranslmed.aba9796 | Citation | Yong J, et al. (2021) Chop/Ddit3 depletion in beta cells alleviates ER stress and corrects hepatic steatosis in mice. Sci Transl Med 13(604) |
| abstractText | Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic beta cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in beta cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in beta cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline Chop gene deletion preserved beta cells in high-fat diet (HFD)-fed mice and in leptin receptor-deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine beta cells conferred therapeutic benefits. First, we showed that Chop deletion in beta cells alleviated beta cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, beta cell-specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that Chop depletion reduces ER Ca(2+) buffering capacity and modulates glucose-induced islet Ca(2+) oscillations, leading to transcriptional changes of ER chaperone profile ("ER remodeling"). Last, we demonstrated that a GLP1-conjugated Chop antisense oligonucleotide strategy recapitulated the reduction in liver triglycerides and pancreatic insulin content. In summary, our results demonstrate that Chop depletion in beta cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D. |
