Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis

作者：Agathe Beaulant, Maya Dia, Bruno Pillot, Marie‐Agnès Chauvin, J. Cao, Christine Durand, Nadia Bendridi, Stéphanie Chanon, Aurélie Vieille‐Marchiset, Claire Crola Da Silva, Stéphanie Patouraux, Rodolphe Anty, Antonio Iannelli, Albert Tran, Philippe Gual, Hubert Vidal, Ludovic Gomez, M. Paillard, Jennifer Rieusset · 发表于：Journal of Hepatology · 年份：2022 · DOI：10.1016/j.jhep.2022.03.017 · 被引用次数：147 · 研究领域：Mitochondrial Function and Pathology、Adipose Tissue and Metabolism、Pancreatic function and diabetes

BACKGROUND & AIMS: Hepatic insulin resistance in obesity and type 2 diabetes was recently associated with endoplasmic reticulum (ER)-mitochondria miscommunication. These contact sites (mitochondria-associated membranes: MAMs) are highly dynamic and involved in many functions; however, whether MAM dysfunction plays a causal role in hepatic insulin resistance and steatosis is not clear. Thus, we aimed to determine whether and how organelle miscommunication plays a role in the onset and progression of hepatic metabolic impairment. METHODS: We analyzed hepatic ER-mitochondria interactions and calcium exchange in a time-dependent and reversible manner in mice with diet-induced obesity. Additionally, we used recombinant adenovirus to express a specific organelle spacer or linker in mouse livers, to determine the causal impact of MAM dysfunction on hepatic metabolic alterations. RESULTS: Disruption of ER-mitochondria interactions and calcium exchange is an early event preceding hepatic insulin resistance and steatosis in mice with diet-induced obesity. Interestingly, an 8-week reversal diet concomitantly reversed hepatic organelle miscommunication and insulin resistance in obese mice. Mechanistically, disrupting structural and functional ER-mitochondria interactions through the hepatic overexpression of the organelle spacer FATE1 was sufficient to impair hepatic insulin action and glucose homeostasis. In addition, FATE1-mediated organelle miscommunication disrupted lipid-related mit...