The liver is a metabolic and immunologic organ: A reconsideration of metabolic decompensation due to infection in inborn errors of metabolism (IEM).
The liver is a metabolic and immunologic organ: A reconsideration of metabolic decompensation due to infection in inborn errors of metabolism (IEM).
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DOI：
10.1016/j.ymgme.2017.06.010
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发表时间：
2017-08
影响因子：
3.8
通讯作者：
McGuire PJ
中科院分区：
文献类型：
--
作者：
Tarasenko TN;McGuire PJ
先天性代谢缺陷（IEM）中的代谢失代偿的特征是代谢状态迅速恶化，导致危及生命的生化紊乱（例如低血糖、高氨血症、酸中毒、器官衰竭）。感染是IEM患者代谢失代偿的主要原因。我们假设感染期间免疫系统的激活导致终末器官代谢的进一步紊乱，从而导致发病率增加。为了解决这个问题，我们建立了由于感染引起的代谢失调的模型系统。利用这些系统，我们描述了代谢失代偿的病理机制以及与感染相关的肝脏代谢储备的变化。首先，我们的研究已经证明，在流感感染期间，肝脏经历了显著的局部先天免疫应答，其调节肝脏代谢。基于这些发现，我们首次提出肝脏作为代谢和免疫器官的作用在IEM感染引起的代谢失代偿的病理生理学中是中心的。肝脏作为主要代谢调节器和负责免疫监视的淋巴器官的双重功能使该器官处于肝毒性的风险中。动员肝脏储备和健康肝脏的再生能力可以补偿这种计算的风险。然而，肝脏先天免疫系统的激活可能是有害的IEM。基于这一论断，旨在调节先天免疫应答的策略可能是肝代谢失代偿治疗中干预的可行靶点。
Metabolic decompensation in inborn errors of metabolism (IEM) is characterized by a rapid deterioration in metabolic status leading to life-threatening biochemical perturbations (e.g. hypoglycemia, hyperammonemia, acidosis, organ failure). Infection is the major cause of metabolic decompensation in patients with IEM. We hypothesized that activation of the immune system during infection leads to further perturbations in end-organ metabolism resulting in increased morbidity. To address this, we established model systems of metabolic decompensation due to infection. Using these systems, we have described the pathologic mechanisms of metabolic decompensation as well as changes in hepatic metabolic reserve associated with infection. First and foremost, our studies have demonstrated that the liver experiences a significant local innate immune response during influenza infection that modulates hepatic metabolism. Based on these findings, we are the first to suggest that the role of the liver as a metabolic and immunologic organ is central in the pathophysiology of metabolic decompensation due to infection in IEM. The dual function of the liver as a major metabolic regulator and a lymphoid organ responsible for immunosurveillance places this organ at risk for hepatotoxicity. Mobilization of hepatic reserve and the regenerative capacity of a healthy liver compensates for this calculated risk. However, activation of the hepatic innate immune system may be deleterious in IEM. Based on this assertion, strategies aimed at modulating the innate immune response may be a viable target for intervention in the treatment of hepatic metabolic decompensation.
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影响因子：
6
作者：
Greenough, TC;Carville, A;Coderre, J;Somasundaran, M;Sullivan, JL;Luzuriaga, K;Mansfield, K
通讯作者：
Mansfield, K
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Chan, PKS
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Saudubray, JM
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通讯作者：
Lai, CL
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2.2
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通讯作者：
Naito, M