Chop/Ddit3 depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice

Abstract

Depletion of Chop in pancreatic β cells optimizes insulin secretion and reduces fatty liver in preclinical models. Fatty liver gets the chop ER stress during early diabetes has been shown to induce the transcription factor C/EBP homologous protein (CHOP), resulting in impaired glycemic control. Yong et al. knocked out Chop specifically in β cells in high-fat diet mice and observed that this reduced both insulin production and subsequent development of fatty liver. Proof-of-concept targeting of Chop using antisense oligonucleotides also reduced insulin content in the mouse model. This study provides preclinical evidence that surplus insulin promotes insulin resistance and fatty liver, and suggests that Chop in β cells may be a therapeutic target for the treatment of T2D. 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 β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin 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 germline Chop gene deletion preserved β 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 β cells conferred therapeutic benefits. First, we showed that Chop deletion in β cells alleviated β cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, β 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 Ca2+ buffering capacity and modulates glucose-induced islet Ca2+ 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 β cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D.