A Key Role for NMN in Alleviating Organelle Miscommunication in HFD Mouse Liver
Introduction
Recent research unveils that hepatic insulin resistance (IR) and steatosis in obesity have a strong association with endoplasmic reticulum (ER)-mitochondria miscommunication. Notably, β-nicotinamide mononucleotide (NMN) can ameliorate hepatic IR and steatosis to regulate obesity via reinforcing the interaction between ER and mitochondria.
About ER-mitochondria miscommunication
ER and mitochondria interact at contact sites called mitochondria-associated membranes (MAMs), where they exchange phospholipids and calcium (Ca2+). MAM acts as a bridge between the ER and mitochondria, participating in the regulation of calcium signaling, lipid homeostasis, mitochondrial dynamics, mitochondrial autophagy, and ER stress response. Disrupting ER-mitochondria communication may induce hepatic IR and steatosis.Research protocol
In vivo, thirty 8-week-old male C57BL/6 J specific pathogen-free mice are fed with normal/high-fat diet (HFD) and normal/NMN-containing drinking water for 30 weeks. During the experiments, the body weight, diet, food intake, appearance, and behavior characteristics of the experimental mice are recorded weekly. A week prior to the end of study, 12-h-fasting mice are subjected with intraperitoneal injection of glucose (2 mg/g body weight) or insulin (0.75 mU/g body weight) for glucose tolerance test and insulin tolerance test, followed by the measurement of glycemia using a glucometer.In vitro, mouse normal hepatocytes NCTC1469 are seeded in 96-well microtiter plates for 12-h culture, then blended with specific palmitic acid (PA) for 36 h to establish the HFD model, and treated with NMN (500, 50, 5, 0.5, and 0.05 μM) for 24 h, followed by detection of physiological indicators.
Regulatory impacts of NMN upon obesity
In vivo, NMN ameliorates hyperlipidemia, hepatic steatosis, liver physiological metabolic damage, liver lipid metabolic abnormalities, and ER-mitochondrial miscommunication in the liver of HFD mice.In vitro, NMN reduces PA-induced lipid accumulation, yet promotes PA-induced mitochondrial-ER communication in NCTC1469 cells.
NMN alleviates organelle miscommunication by increasing MAMs in HFD mice liver. Concretely, NMN ameliorates mitochondrial dysfunction and ER oxidative stress in the liver of HFD mice by increasing hepatic nicotinamide adenine dinucleotide (NAD+) level. This effect increases the MAMs between ER and mitochondria, thereby promoting intracellular ATP production and mitigating lipid metabolic disturbances in the liver of HFD mice.
Conclusion
NMN enhances the dynamic properties of MAMs to increase the communication between mitochondria and ER, ultimately reversing HFD-induced glycolipid metabolic disorder, IR and hepatic steatosis.Reference
[1] Beaulant A, Dia M, Pillot B, et al. Endoplasmic reticulum-mitochondria miscommunication is an early and causal trigger of hepatic insulin resistance and steatosis. J Hepatol. 2022;77(3):710-722. DOI:10.1016/j.jhep.2022.03.017[2] Lam BCC, Lim AYL, Chan SL, et al. The impact of obesity: a narrative review. Singapore Med J. 2023;64(3):163-171. DOI: 10.4103/singaporemedj.SMJ-2022-232
[3] Li Y, Tian X, Yu Q, et al. Alleviation of hepatic insulin resistance and steatosis with NMN via improving endoplasmic reticulum-mitochondria miscommunication in the liver of HFD mice. Biomed Pharmacother. Published online May 3, 2024. DOI:10.1016/j.biopha.2024.116682
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