ABSTRACT
AF6, a known polarity protein, contributes to the maintenance of homeostasis while ensuring tissue architecture, repair, and integrity. Mice that lack AF6 display embryonic lethality owing to cell-cell junction disruption. However, we show AF6 promotes necroptosis via regulating the ubiquitination of RIPK1 by directly interact with the intermediate domain of RIPK1, which was mediated by the deubiquitylase enzyme USP21. Consistently, while injection of mice with an adenovirus providing AF6 overexpression resulted in accelerated TNFα-induced necroptosis-mediated mortality in vivo, we observed that mice with hepatocyte-specific deletion of AF6 prevented hepatocytes from necroptosis and the subsequent inflammatory response in various liver diseases model, including non-alcoholic steatohepatitis (NASH) and the systemic inflammatory response syndrome (SIRS).Together, these data suggest that AF6 represents a novel regulator of RIPK1-RIPK3 dependent necroptotic pathway. Thus, the AF6-RIPK1-USP21 axis are potential therapeutic targets for treatment of various liver injuries and metabolic diseases.
Subject(s)
Liver Diseases , Necroptosis , Animals , Mice , Apoptosis/physiology , Hepatocytes/metabolism , Liver Diseases/genetics , Necroptosis/physiology , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolism , Systemic Inflammatory Response Syndrome , UbiquitinationABSTRACT
Objectives To compare the differences in intestinal phylum firmicutes between elderly patients with type 2 diabetes (T2DM)and the healthy elder people.Methods 37 elderly patients with T2DM and 69 healthy controls in Shaoxin city were recruited.DNA of phylum firmicutes from fecal samples was extracted.The real-time quantitative PCR was used with special primers for bacterial genus including Faecalibacterium prausnitzii,Eubacterium rectale,Clostridium leptum,and Peptostrepyococc.The differences in content of different bacteria between two groups were analyzed and compared.Results In healthy elderly group versus the elder patient with T2DM,the contents of intestinal phylum firmicutes were[(6.22±1.41) × 107 versus(5.41± 1.40) × 107,t=2.83,P=0.006] in Eubacterium rectale,[(7.46 ± 0.98) × 107 versus (6.96 ± 1.40) × 107),t =2.13,P =0.036] in Faecali bacterium prausnitzii,[(7.89±0.89) × 107 versus(7.46±1.11) × 107,t=2.15,P=0.034]in Clostridium leptum,and[(4.86 ± 1.33) × 107 versus (4.21 ± 1.24) × 107,t=2.45,P =0.016] in Peptostrepyococc,which showed that the contents of intestinal phylum firmicutes were less in T2DM group than in healthy elderly group.Conclusions There are some differences in intestinal flora between the elderly patients with T2DM and healthy people.These intestinal flora may play an important role in the development of T2DM.This study may provide new evidences for probiotic treatment of T2DM.
