Chop/Ddit3depletion in β-cells alleviates ER stress and corrects hepatic steatosis

Abstract

AbstractType 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 β cells is enhanced, which can lead to proinsulin (ProIns) misfolding that aggravates endoplasmic reticulum (ER) homeostasis in β cells. Moreover, increased insulin in the circulation may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germlineChopgene deletion preserved β cells in high fat diet (HFD) fed mice and in leptin receptor-deficientdb/dbmice. In the current study, we further investigated whether targetingChop/Ddit3specifically in murine β cells confers therapeutic benefits. First, we show thatChopdeletion in β cells alleviates β cell ER stress and delays glucose-stimulated insulin secretion (GSIS) in HFD fed mice. Second, importantly, β cell-specificChopdeletion prevented liver steatosis and hepatomegaly in aged HFD fed mice without affecting basal glucose homeostasis. Third, we provide the first mechanistic evidence that ER remodeling secondary toChopdeletion modulates glucose-induced islet Ca2+oscillations. Finally, using state-of-the-art GLP1-conjugatedChopAntiSense Oligonucleotides (GLP1-ChopASO), we demonstrated that theChopdeletion induced GSIS change is a long term complex event in β cells. In summary, our results demonstrate thatChopdepletion in β cells is a new therapeutic strategy to alleviate dysregulated insulin secretion and the consequently fatty liver disease in T2D.