Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza.
Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza.
复制标题
DOI：
10.1016/j.bbadis.2015.08.021
复制
发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
McGuire PJ
中科院分区：
文献类型：
--
作者：
Tarasenko TN;Singh LN;Chatterji-Len M;Zerfas PM;Cusmano-Ozog K;McGuire PJ
在对感染的反应中，患有先天性代谢缺陷的患者可能会出现称为代谢失代偿的功能恶化。这种代谢稳态破坏的生化标志是疾病特异性的，可能包括酸中毒、高氨血症或低血糖。在我们小组先前发表的一个模型系统中，我们注意到在流感感染期间，小鼠显示出参与氮代谢的肝线粒体酶的抑制。基于这些发现，我们假设这种正常的适应可能会扩展到其他代谢途径，因此可能会影响各种先天性代谢缺陷。由于肝脏是先天性代谢缺陷的关键器官，我们在感染流感的C57 Bl/6小鼠中使用质谱法进行了肝脏的非靶向代谢组学分析，以表征代谢适应。代谢组学数据的途径分析显示CoA合成减少，长链脂肪酰CoA和肉毒碱种类减少。这些代谢适应与肝脏长链β-氧化mRNA和蛋白的抑制相一致。令我们惊讶的是，所观察到的代谢变化与肝脏先天免疫反应一起发生，如转录谱和流式细胞术所示。通过采用免疫调节策略来消耗枯否细胞，我们能够改善参与β-氧化的多个基因的表达。基于这些发现，我们首次提出肝脏作为免疫器官的作用在呼吸道病毒感染引起的先天性代谢缺陷的肝脏代谢失代偿的病理生理学中是中心的。
In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.
登录
查看更多内容
影响因子：
30.5
作者：
Lee, Woo-Yong;Moriarty, Tara J.;Kubes, Paul
通讯作者：
Kubes, Paul
影响因子：
3.5
作者：
Houten, Sander M.;Herrema, Hilde;Wanders, Ronald J. A.
通讯作者：
Wanders, Ronald J. A.
影响因子：
4.2
作者：
de Baulny, HO;Benoist, JF;Saudubray, JM
通讯作者：
Saudubray, JM
DOI：
10.1016/0167-4889(95)00188-3
发表时间：
1996-03-27
影响因子：
5.1
作者：
Kitade, H;Kanemaki, T;Okumura, T
通讯作者：
Okumura, T
DOI：
10.1093/bioinformatics/btp101
发表时间：
2009-04-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Bindea G;Mlecnik B;Hackl H;Charoentong P;Tosolini M;Kirilovsky A;Fridman WH;Pagès F;Trajanoski Z;Galon J
通讯作者：
Galon J