巨噬细胞
酮体
肝细胞
肝纤维化
代谢组
代谢组学
纤维化
生物化学
生物
新陈代谢
线粒体
化学
细胞生物学
内科学
代谢物
体外
医学
生物信息学
作者
Patrycja Puchalska,Shannon E. Martin,Xiaojing Huang,Justin Lengfeld,Bence Dániel,Mark J. Graham,Xianlin Han,László Nagy,Gary J. Patti,Peter A. Crawford
出处
期刊:Cell Metabolism
[Elsevier]
日期:2018-11-15
卷期号:29 (2): 383-398.e7
被引量:100
标识
DOI:10.1016/j.cmet.2018.10.015
摘要
Metabolic plasticity has been linked to polarized macrophage function, but mechanisms connecting specific fuels to tissue macrophage function remain unresolved. Here we apply a stable isotope tracing, mass spectrometry-based untargeted metabolomics approach to reveal the metabolome penetrated by hepatocyte-derived glucose and ketone bodies. In both classically and alternatively polarized macrophages, [13C]acetoacetate (AcAc) labeled ∼200 chemical features, but its reduced form D-[13C]β-hydroxybutyrate (D-βOHB) labeled almost none. [13C]glucose labeled ∼500 features, and while unlabeled AcAc competed with only ∼15% of them, the vast majority required the mitochondrial enzyme succinyl-coenzyme A-oxoacid transferase (SCOT). AcAc carbon labeled metabolites within the cytoplasmic glycosaminoglycan pathway, which regulates tissue fibrogenesis. Accordingly, livers of mice lacking SCOT in macrophages were predisposed to accelerated fibrogenesis. Exogenous AcAc, but not D-βOHB, ameliorated diet-induced hepatic fibrosis. These data support a hepatocyte-macrophage ketone shuttle that segregates AcAc from D-βOHB, coordinating the fibrogenic response to hepatic injury via mitochondrial metabolism in tissue macrophages.
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