Metabolic Adaptation Establishes Disease Tolerance to Sepsis. Cell 2017, 169:1263-1275.

報告日期: 2017/11/14
報告時間: 15:10/16:00
報告學生: 劉建聰
講評老師: 楊倍昌
附件下載: 下載[1668-1506045864-1.pdf] 

Metabolic Adaptation Establishes Disease Tolerance to Sepsis

Sebastian Weis, Ana Rita Carlos, et al.            Cell 2017, 169:1263-1275.

Presenter:Chien-Tsung Liu                            Date/Time: 2017/11/14 15:10 -16:00

Commentator:Bei-Chang Yang, Ph.D.             Location:Room 602, Med College Building

Abstract:

Sepsis is a life-threatening disorder that is caused by an unbalanced host response to infections. By infections, the invading pathogens disturb host immune systems, metabolism, tissue homeostasis, etc. These result in multiple organ failure or septic shock and high mortality in sepsis patients.(Hotchkiss et al., 2016) During the proliferation of pathogens, iron serves as an essential nutrient to support growth; hence, pathogens evolve specialized iron-uptake systems to acquire iron from cell-free heme. To prevent pathogens obtaining iron from heme, microphages and hepatocytes clear extracellular heme by stress-induced heme oxygenase 1 (HO-1). However, the HO-1 mediated heme catabolism produces labile iron and reactive oxidative species (ROS). The accumulation of oxidative stress eventually leads to programmed cell death (PCD) in hepatocytes and tissue damage. This iron induced cytotoxic effect can be protected by ferritin heavy chain (FTH) through its ferroxidase activity. FTH converts labile iron into a more stable form and prevents intracellular free iron by its binding ability.(Gozzelino and Soares, 2014)

Recently, the appropriate expression of FTH in sepsis patients showed a better survival outcome and increased the disease tolerance in mice malaria models, which also showed hemolysis. (Gozzelino et al., 2012) Therefore, based on the above studies, the authors wondered the role of FTH in sepsis. To verify this question, the authors performed cecal ligation and puncture (CLP), a common sepsis model, in FTH knock-out mice. Their results showed that loss of FTH elevated mortality and caused hypoglycemia in CLP mice, but the pathogen load was no significant difference in control and CLP mice. They further confirmed that FTH modulated glucose metabolism via regulating glucose-6-phosphatase catalytic subunit 1 (G6PC1) expression level and activity in sepsis mice. Just like FTH deficiency mice, mice lacking G6PC1 decreased blood glucose level and survival after injection of heme or inducing sepsis. Administration of appropriate amount of glucose, apoferritin and antioxidants restored blood glucose level back to normoglycemia and disease tolerance in CLP mice. Based on the findings of this study, the authors suggested that FTH regulates glucose metabolism and establishes disease tolerance in response to sepsis-induced hemolysis. Controlling blood glucose level or injecting iron-free transferrin and antioxidants might be a therapeutic approach in clinical.

References:

Gozzelino, R., Andrade, B.B., Larsen, R., Luz, N.F., Vanoaica, L., Seixas, E., Coutinho, A., Cardoso, S., Rebelo, S., Poli, M., et al. (2012). Metabolic adaptation to tissue iron overload confers tolerance to malaria. Cell Host Microbe 12, 693-704.

Gozzelino, R., and Soares, M.P. (2014). Coupling heme and iron metabolism via ferritin H chain. Antioxid Redox Signal 20, 1754-1769.

Hotchkiss, R.S., Moldawer, L.L., Opal, S.M., Reinhart, K., Turnbull, I.R., and Vincent, J.L. (2016). Sepsis and septic shock. Nat Rev Dis Primers 2, 16045.