Beaulant 2022 J Hepatol
| Beaulant A, Dia M, Pillot B, Chauvin MA, Ji-Cao J, Durand C, Bendridi N, Chanon S, Vieille-Marchiset A, Da Silva CC, Patouraux S, Anty R, Iannelli A, Tran A, Gual P, Vidal H, Gomez L, Paillard M, Rieusset J (2022) Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis. https://doi.org/10.1016/j.jhep.2022.03.017 |
» J Hepatol 77:710-22. PMID: 35358616 Open Access
Beaulant Agathe, Dia Maya, Pillot Bruno, Chauvin Marie-Agnes, Ji-Cao Jingwei, Durand Christine, Bendridi Nadia, Chanon Stephanie, Vieille-Marchiset Aurelie, Da Silva Claire Crola, Patouraux Stephanie, Anty Rodolphe, Iannelli Antonio, Tran Albert, Gual Philippe, Vidal Hubert, Gomez Ludovic, Paillard Melanie, Rieusset Jennifer (2022) J Hepatol
Abstract: 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.
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.
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 mitochondrial oxidative metabolism and induced hepatic steatosis. Conversely, reinforcement of ER-mitochondria interactions through hepatic expression of a synthetic linker prevented diet-induced glucose intolerance after 4 weeks' overnutrition. Importantly, ER-mitochondria miscommunication was confirmed in the liver of obese patients with type 2 diabetes, and correlated with glycemia, HbA1c and HOMA-IR index.
ER-mitochondria miscommunication is an early causal trigger of hepatic insulin resistance and steatosis, and can be reversed by switching to a healthy diet. Thus, targeting MAMs could help to restore metabolic homeostasis.
• Bioblast editor: Plangger M
Labels: MiParea: Respiration
Pathology: Diabetes, Obesity
Organism: Mouse Tissue;cell: Liver Preparation: Permeabilized cells, Intact cells
Coupling state: ET
HRR: Oxygraph-2k
2022-11
