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The NRF2‑PGC‑1Β Pathway Activates Kynurenine Aminotransferase 4 Via

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The NRF2‑PGC‑1Β Pathway Activates Kynurenine Aminotransferase 4 Via MOLECULAR MEDICINE REPORTS 18: 2467-2475, 2018 The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model YUSUKE ISHIDA1*, HIDETOSHI FUJITA2,3*, SATOKO ARATANI2,3, MIYUKI CHIJIIWA1, NOBORU TANIGUCHI4, MAHO YOKOTA2, YUKIHIKO OGIHARA1, NAOMI UOSHIMA1, FUMIAKI NAGASHIMA1, HIROYUKI UCHINO1 and TOSHIHIRO NAKAJIMA2,3,5-10 1 2 Department of Anesthesiology, Tokyo Medical University Hospital, Tokyo 160‑0023; Institute of Medical Science, 3Department of Future Medical Science, Tokyo Medical University, Tokyo 160‑8402; 4Department of Medicine of Sensory and Motor Organs, Division of Orthopedic Surgery, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889‑1692; 5Integrated Gene Editing Section (iGES); 6Medical Research Center; 7Industry‑University Cooperation (BioMimetics Sympathies Inc.), Tokyo Medical University Hospital, Tokyo 160‑0023; 8Institute of Medical Science, 9 St. Marianna University School of Medicine, Kawasaki, Kanagawa 216‑8511; Department of Biomedical Engineering, 10 Osaka Institute of Technology, Osaka 535‑8585; Bayside Misato Medical Center, Kochi 781‑0112, Japan Received June 15, 2017; Accepted March 15, 2018 DOI: 10.3892/mmr.2018.9175 Abstract. Sepsis-associated encephalopathy (SAE) is a septic Syvn1‑deficient mice. KYN is converted to kynurenic systemic inflammatory response syndrome of which the precise acid (KYNA) by kynurenine aminotransferases (KATs), associated mechanisms remain unclear. Synoviolin (Syvn1) is which has a neuroprotective effect. The expression of KAT4 an E3 ubiquitin ligase involved in conditions associated with was significantly increased in Syvn1‑deficient mice compared chronic inflammation, including rheumatoid arthritis, obesity, to that in wild‑type mice. Promoter analysis demonstrated fibrosis and liver cirrhosis. However, the role of Syvn1 in acute that Syvn1 knockdown induced the KAT4 promoter activity, inflammation is not clear. The aim of the present study was to as assessed by luciferase reporter activity, whereas Syvn1 investigate the role of Syvn1 in a septic mouse model induced overexpression repressed this activity in a dose‑dependent by cecal ligation/perforation (CLP). Metabolome analysis manner. Furthermore, the KAT4 promoter was significantly revealed that kynurenine (KYN), a key factor for the develop- activated by the transcriptional factors, NF‑E2‑related factor 2 ment of neuroinflammation, was increased in CLP‑induced and peroxisome proliferator‑activated receptor coactivator 1β, septic mice. Notably, KYN was not detected in CLP‑induced which are targets of Syvn1‑induced degradation. In conclusion, the results of the current study demonstrates that the repres- sion of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLP‑induced mouse Correspondence to: Professor Toshihiro Nakajima, Institute model of sepsis, and that Syvn1 is a potential novel target for of Medical Science, Tokyo Medical University, 6‑1‑1 Shinjuku, the treatment of SAE. Shinjuku, Tokyo 160‑8402, Japan E‑mail: marlin@tokyo‑med.ac.jp Introduction *Contributed equally Sepsis is a form of systemic inflammation caused by an infection, and multiple organ failure is known to occur when Abbreviations: Syvn1, synoviolin; SAE, sepsis‑associated this condition intensifies. Clinical studies demonstrated that encephalopathy; CLP, cecal ligation/perforation; KYN, kynurenine; the central nervous system might be one of the first organs KYNA, kynurenic acid; KATs, kynurenine aminotransferases; affected by sepsis. Sepsis‑associated encephalopathy (SAE), PGC-1β, Peroxisome proliferator‑activated receptor coactivator 1β; QA, quinolinic acid; 3‑HAA, 3‑hydroxykynurenine; SPF, specific characterized by diffuse cerebral dysfunction, is secondary to pathogen‑free sepsis and is related to increased morbidity and mortality (1,2). Clinical symptoms of SAE are delirium, fluctuating changes Key words: synoviolin, NRF2, PGC‑1β, kynurenine, septic mouse in mental status, lack of attention, and disorganized thinking. model, kynurenine aminotransferase 4, E3 ligase Encephalopathy of variable severity occurs in 9‑71% of septic patients, and those with central nervous disorders have the worst prognosis in terms of cognitive and motor function. 2468 ISHIDA et al: ROLE OF Syvn1 IN SEPTIC MOUSE MODEL In addition, it has been reported that the mortality rate of revealed that Syvn1 ablation mediates the activation of trypto- septic patients with SAE is approximately twice that of septic phan metabolism via KAT4 gene expression. patients without SAE; moreover, the mortality rate increases to 63% when patients with SAE present with a Glasgow Coma Materials and methods Scale (GCS) value of 3‑8 (1,2). Although several mechanisms including inflammation or the disturbance of neurotransmis- Mice. All procedures involving animals were performed sion disturbance, have been proposed, the precise mechanisms in accordance with institutional and national guidelines responsible for sepsis‑induced cognitive impairment have not for animal experimentation, and were approved by the been fully elucidated. Institutional Animal Care and Use Committee of Tokyo The kynurenine (KYN) pathway is well known to be a Medical University (#S‑24021). Mice were kept in specific major mechanism of tryptophan catabolism, and it is activated pathogen free (SPF) under standard conditions (20‑26˚C during neuroinflammation during several neurodegenerative temperature; 40‑65% humidity) with a 12‑h light/12‑h dark diseases (3,4) such as SAE (5). Tryptophan is converted cycle. F‑1 Foods (5.1% fat, 21.3% protein) were purchased to KYN, and KYN is converted into three intermediates, from Funabashi farm (Chiba, Japan). All mice used in the quinolinic acid (QA), 3‑hydroxykynurenine (3‑HAA), and study were of the C57BL/6J background. Heterozygous Syvn1 kynurenic acid (KYNA) via two different pathways (Fig. 1). mice and tamoxifen (Tam)‑inducible Syvn1 knockout mice 3‑HAA and QA are neurotoxic, whereas KYNA is neuro- were previously described (9,13). protective. The relative balance between the two branches of this pathway might play an important role in the devel- Sepsis model. Male C57/BL6 mice at 7‑9 weeks of age were opment of neuroinflammation. The conversion to KYNA is anesthetized with 4‑5% sevoflurane and a middle abdominal catalyzed by kynurenine aminotransferases (KATs), which incision was made along the ventral surface of the abdomen have been detected in the brain and peripheral tissues such to expose the cecum. Before perforation, feces were gently as the skeletal muscle (6,7). Recent studies showed that the relocated towards the distal cecum. The cecum was ligated peroxisome proliferator‑activated receptor (PPAR)‑PPAR at 5 mm from the distal end and then punctured once with a coactivator‑1 (PGC‑1) pathway induces skeletal muscle 21‑gauge needle, allowing the exposure of feces (cecal ligation KAT expression during exercise (7,8). The analysis of and puncture; CLP). A small droplet of feces was then gently PGC-1α1 skeletal muscle‑specific transgenic mice showed squeezed through both sides of the puncture. The cecum was that increased expression of skeletal muscle KATs induced returned to the peritoneal cavity with careful attention to ensure KYN metabolism. Synthesis of KYNA was enhanced and that feces did not contaminate the margins of the abdominal the accumulation of KYN was reduced, thereby protecting and skin wound. The muscle and skin incision were closed against stress‑induced depression (7). with 3‑0 black silk. This model represents a high‑grade sepsis Among several hundreds of E3 ubiquitin ligases, synovi- with 100% mortality in 72 h (22). Mice received a subcuta- olin (Syvn1), identified from the cDNA of rheumatoid synovial neous injection of pre‑warmed saline solution (37˚C; 5 ml per cells, is the only known regulator of PGC‑1β ubiquitina- 100 g body weight). Mice receiving sham surgery underwent tion (9). We recently demonstrated that Syvn1 interacts with the same procedure except that the cecum was neither ligated PGC-1β and induces its degradation (9). Global elimination nor punctured (sham group; S). At each experimental time of Syvn1 in post‑neonatal mice is associated with weight loss point after performing the procedure, mice were euthanized and reduced white adipose tissue through enhanced energy by cervical dislocation, and brain and skeletal muscle tissue expenditure, which is mediated by the function of PGC‑1β (9). samples were obtained. PGC-1β and PGC-1α share extensive sequence identity to each other (10,11), and the primary structure of PGC‑1β has Measurement of metabolites. Brain tissues were obtained several unique features of primary structure such as LXXLL at 18 h after the CLP procedure (n=2 for each group). in its middle portion and the absence of a proline‑rich region Approximately 20 mg of frozen brain tissues were immersed at the C‑terminus. Knockout studies have also suggested into 1,500 µl of 50% acetonitrile/Milli‑Q water containing functional differences between PGC‑1α and PGC-1β, such internal standards (H3304‑1002; Human Metabolome as lethality (12). We previously demonstrated that Syvn1 is Technologies, Inc., Tsuruoka, Japan) at 0˚C in order to inac- involved in the development of rheumatoid arthritis, fibrosis, tivate enzymes. The tissue was homogenized three times at limb girdle muscular dystrophy, and liver cirrhosis (13-17). 1,500 rpm for 120s using a tissue homogenizer
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