脂肪性肝炎
糖酵解
生物能学
安普克
下调和上调
生物
PI3K/AKT/mTOR通路
呼吸链
氧化磷酸化
线粒体
脂肪肝
活性氧
线粒体呼吸链
细胞生物学
生物化学
内科学
新陈代谢
信号转导
医学
激酶
蛋白激酶A
疾病
基因
作者
Moris Sangineto,Martina Ciarnelli,Tommaso Colangelo,Archana Moola,Vidyasagar Naik Bukke,Loren Duda,Rosanna Villani,A. Romano,Stefania Giandomenico,Hina Kanwal,Gaetano Serviddio
标识
DOI:10.1016/j.xcrm.2024.101564
摘要
Monocytes (Mos) are crucial in the evolution of metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), and immunometabolism studies have recently suggested targeting leukocyte bioenergetics in inflammatory diseases. Here, we reveal a peculiar bioenergetic phenotype in circulating Mos of patients with MASH, characterized by high levels of glycolysis and mitochondrial (mt) respiration. The enhancement of mt respiratory chain activity, especially complex II (succinate dehydrogenase [SDH]), is unbalanced toward the production of reactive oxygen species (ROS) and is sustained at the transcriptional level with the involvement of the AMPK-mTOR-PGC-1α axis. The modulation of mt activity with dimethyl malonate (DMM), an SDH inhibitor, restores the metabolic profile and almost abrogates cytokine production. Analysis of a public single-cell RNA sequencing (scRNA-seq) dataset confirms that in murine models of MASH, liver Mo-derived macrophages exhibit an upregulation of mt and glycolytic energy pathways. Accordingly, the DMM injection in MASH mice contrasts Mo infiltration and macrophagic enrichment, suggesting immunometabolism as a potential target in MASH.
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