Korean J Gastroenterol.  2014 Oct;64(4):182-188. 10.4166/kjg.2014.64.4.182.

Necroptosis in Liver and Pancreatic Diseases

• Yoon JH
• Jun DW
• Choi HS

• KMID: 1979202
• DOI: http://doi.org/10.4166/kjg.2014.64.4.182

Abstract

Cell death is an integral part of life of an organism that is necessary to maintain organs and tissues. Apoptosis, autophagy, and necrosis were noted as three morphologically distinct types of cell death. Apoptosis is a well identified process that is driven by programmed molecular mechanism. Until now, the investigators believed that necrosis was not a programmed molecular event. However, recently, an alternative death pathway called 'necroptosis' was delineated and proposed as a form of 'programmed necrosis'. According to the recent recommendations by the Nomenclature Committee of Cell Death, this term denotes necrotic cell death dependent on receptor-interacting protein kinase (RIPK3). Its role in a variety of diseases, such as ischemia-perfusion injury, infection, inflammatory bowel disease, pancreatitis, steatohepatitis etc., is being elucidated. Necroptosis is currently attracting the attention of the scientific community. Herein we discuss the clinical implications and the role of necroptosis in gastrointestinal tract focusing on liver and pancreatic diseases.

Keyword

Cell death; Necroptosis; Necrosis; Receptor-interacting protein kinase; Tumor necrosis factor-alpha

MeSH Terms

Apoptosis
Autophagy
Cell Death
Fatty Liver
Gastrointestinal Tract
Humans
Inflammatory Bowel Diseases
Liver*
Necrosis
Pancreatic Diseases*
Pancreatitis
Protein Kinases
Research Personnel
Tumor Necrosis Factor-alpha
Protein Kinases
Tumor Necrosis Factor-alpha

Figure

• 

  Fig. 1. Types of cell death. Programmed cell death can be divided into apoptosis and regulated necrosis. There are two subtypes of apoptosis: intrinsic apoptosis mediated by caspase 9 vs. extrinsic apoptosis mediated by caspase 8. As for regulated necrosis, there are several subtypes including necroptosis regulated by RIPK1, RIPK3 and MLKL, and MPT mediated by cyclophilin D, In addition to necroptosis and MPT, we suspect that there would be another regulated necrosis pathway. Note: The classification shown is not a confirmative one but has been presented for descriptive purposes. MPT, mitochondrial permeability transition; LC3, light chain 3; Atg, autophagy-related protein; LAMP, lysosomal associated membrane protein; RIPK, receptor-interacting protein kinase; MLKL, mixed lineage kinase domain-like; PARP1, poly [ADP-ribose] polymerase 1.

• 

  Fig. 2. Signaling pathway of apoptosis and necroptosis induced by death receptor such as TNF receptor. Stimulation of cells with TNF leads to recruitment of TRADD, FADD, and RIPK1 to TNF receptor. The different outcomes are determined by distinct TNF receptor-associated signaling complexes. FADD and caspase-8 are the essential adapter proteins involved in apoptosis. Under conditions of impaired apoptosis, TNF receptor-1 can induce necroptosis, which involves RIPK1 and RIPK3 kinases. RIPK1 and RIPK3 engage in physical and functional interactions with MLKL to form a multiprotein complex called necrosome. The necrosome stimulates regulated necrosis at the mitochondrial level by inhibiting adenine nucleotide transferase, by exacerbating glutaminolysis (not shown) and hence, inducing the overgeneration of reactive oxygen species (ROS), and by promoting mitochondrial fragmentation. Consequently, cell death is induced by necroptosis. TNFR, tumor necrosis factor (TNF) receptor; TRAILR, TNF-related apoptosis-inducing ligand receptor; NF, nuclear factor; NEMO, NF-κ B essential modulator; FADD, Fas associated death domain; cIAP, cellular inhibitor of apoptosis; RIPK, receptor-interacting protein kinase; TRADD, TNF-recptor-associated death domain; zVAD fluoromethyl ketone, benzyloxycarbonyl-Val-Ala-Asp[OMe] fluoromethyl ketone; MLKL, mixed lineage kinase domain-like; MPT, mitochondrial permeability transition; FLIP, Fas-associated death domain-like interleukin-1β-converting enzyme [FLICE]-like inhibitory proteins.

Reference

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