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Effects of elafibranor on liver fibrosis and gut barrier function in a mouse model of alcohol-associated liver disease

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World Journal of Gastroenterology 2024年第28期30卷 3428-3446页

作者： Aritoshi Koizumi Kosuke Kaji Norihisa Nishimura Shohei Asada Takuya Matsuda Misako Tanaka Nobuyuki Yorioka Yuki Tsuji Koh Kitagawa Shinya Sato tadashi namisaki Takemi Akahane Hitoshi Yoshiji Department of Gastroenterology Nara Medical UniversityKashihara 634-8521Japan

BACKGROUND Alcohol-associated liver disease(ALD)is a leading cause of liver-related morbidity and mortality,but there are no therapeutic targets and modalities to prevent ALD-related liver *** proliferator activated receptor(PPAR)α and δ play a key role in lipid metabolism and intestinal barrier homeostasis,which are major contributors to the pathological progression of ***,elafibranor(EFN),which is a dual PPARαand PPARδagonist,has reached a phase III clinical trial for the treatment of metabolic dysfunctionassociated steatotic liver disease and primary biliary ***,the benefits of EFN for ALD treatment is *** To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse *** ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol(EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly(1 mL/kg)for 8 ***(3 and 10 mg/kg/day)was orally administered during the experimental *** and molecular analyses were performed to assess the effect of EFN on steatohepatitis,fibrosis,and intestinal barrier *** EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based *** The hepatic steatosis,apoptosis,and fibrosis in the ALD mice model were significantly attenuated by EFN *** promoted lipolysis and β-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells,primarily through PPARα***,EFN inhibited the Kupffer cell-mediated inflammatory response,with blunted hepatic exposure to lipopolysaccharide(LPS)and toll like receptor 4(TLR4)/nuclear factor kappa B(NF-κB)*** improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory *** protective effect on intestinal bar

关键词： Liver fibrosis Ethanol Gut barrier function Apoptosis Autophagy Peroxisome proliferator activated receptor

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ADAMTS13 and von Willebrand factor are useful biomarkers for sorafenib treatment efficiency in patients with hepatocellular carcinoma

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World Journal of Gastrointestinal Oncology 2019年第5期11卷 424-435页

作者： Hiroaki Takaya tadashi namisaki Naotaka Shimozato Kosuke Kaji Mitsuteru Kitade Kei Moriya Shinya Sato Hideto Kawaratani Takemi Akahane Masanori Matsumoto Hitoshi Yoshiji Third Department of Internal Medicine Nara Medical University Department of Blood Transfusion Medicine Nara Medical University

BACKGROUND Many advanced hepatocellular carcinoma(HCC) patients are receiving sorafenib treatment. Sorafenib reportedly improves overall survival(OS) significantly in patients with HCC. Prediction of sorafenib response and prognosis in patients with HCC receiving sorafenib treatment are important due to the potentially serious side effects of sorafenib. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13(ADAMTS13) and von Willebrand factor(VWF) are associated with the pathophysiology of liver cirrhosis and HCC through their roles in hypercoagulability; they are also associated with angiogenesis via vascular endothelial growth factor(VEGF). The imbalance between ADAMTS13 and VWF was associated with prognosis of various cancers in patients undergoing *** To investigate ADAMTS13 and VWF as potential biomarkers for sorafenib response and prognosis in patients with HCC receiving sorafenib *** Forty-one patients with HCC receiving sorafenib treatment were included in this study. The initial daily sorafenib dose was 400 mg in all patients. ADAMTS13 activity(ADAMTS13:AC), VWF antigen(VWF:Ag), VEGF levels were determined by enzyme-linked immunosorbent assay. Univariate andmultivariate analyses were used to determine predictive factors for sorafenib response and prognosis in patients with HCC receiving sorafenib *** ADAMTS13:AC was significantly higher in patients with stable disease(SD),partial response(PR), and complete response(CR) than in those with progressive disease(PD)(P < 0.05). In contrast, VWF:Ag and the VWF:Ag/ADAMTS13:AC ratio were significantly lower in patients with SD, PR, and CR than in those with PD(P < 0.05 for both). Multivariate analysis showed that the VWF:Ag/ADAMTS13:AC ratio was the only predictive factor for sorafenib response and ADAMTS13:AC was the only prognostic factor in patients with HCC receiving sorafenib treatment. The patients with a low ADAMTS13:AC(<78.0) had significantly h

关键词： ADAMTS13 Von Willebrand factor Biomarkers Hepatocellular carcinoma Sorafenib

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Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity

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World Journal of Gastroenterology 2017年第47期23卷 8355-8366页

作者： Kosuke Kaji Hiroaki Takaya Soichiro Saikawa Masanori Furukawa Shinya Sato Hideto Kawaratani Mitsuteru Kitade Kei Moriya tadashi namisaki Takemi Akahane Akira Mitoro Hitoshi Yoshiji Third Department of Internal Medicine Nara Medical University

AIM To determine the efficacy of rifaximin for hepatic encephalopathy(HE) with the linkage of gut microbiome in decompensated cirrhotic *** Twenty patients(12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis(Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test(NCT)-A. Changes in whole blood endotoxin activity(EA) was analyzed by endotoxinactivity assay. Fecal microbiome was assessed by 16 S ribosome RNA(rR NA) gene *** Treatment with rifaximin for 4 wk improved hyperammonemia(from 90.6 ± 23.9 μg/d L to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT(from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced(from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels(r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator(Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups(3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were *** Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.

关键词： gut microbiome Hepatic encephalopathy Liver cirrhosis Endotoxin Rifaximin

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Dual therapy with zinc acetate and rifaximin prevents from ethanolinduced liver fibrosis by maintaining intestinal barrier integrity

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World Journal of Gastroenterology 2021年第48期27卷 8323-8342页

作者： Yuki Fujimoto Kosuke Kaji Norihisa Nishimura Masahide Enomoto Koji Murata Soichi Takeda Hiroaki Takaya Hideto Kawaratani Kei Moriya tadashi namisaki Takemi Akahane Hitoshi Yoshiji Department of Gastroenterology Nara Medical UniversityKashihara 6348521NaraJapan

BACKGROUND Hepatic overload of gut-derived lipopolysaccharide dictates the progression of alcoholic liver disease(ALD)by inducing oxidative stress and activating Kupffer cells and hepatic stellate cells through toll-like receptor 4 ***,targeting the maintenance of intestinal barrier integrity has attracted attention for the treatment of *** acetate and rifaximin,which is a nonabsorbable antibiotic,had been clinically used for patients with cirrhosis,particularly those with hepatic encephalopathy,and had been known to improve intestinal barrier ***,only few studies focused on their efficacies in preventing the ALD-related fibrosis *** To investigate the effects of a combined zinc acetate with rifaximin on liver fibrosis in a mouse ALD *** To induce ALD-related liver fibrosis,female C57BL/6J mice were fed a 2.5%(v/v)ethanol-containing Lieber-DeCarli liquid diet and received intraperitoneal carbon tetrachloride(CCl4)injection twice weekly(1 mL/kg)for 8 *** acetate(100 mg/L)and/or rifaximin(100 mg/L)were orally administered during experimental *** steatosis,inflammation and fibrosis as well as intestinal barrier function were evaluated by histological and molecular ***,the direct effects of both agents on Caco-2 barrier function were assessed by in vitro *** the ethanol plus CCl4-treated mice,combination of zinc acetate and rifaximin attenuated oxidative lipid peroxidation with downregulation of Nox2 and *** combination significantly inhibited the Kupffer cells expansion and the proinflammatory response with blunted hepatic exposure of lipopolysaccharide and the toll-like receptor 4/nuclear factor kB ***,liver fibrosis and hepatic stellate cells activation were efficiently suppressed with downregulation of Mmp-2,-9,-13,and *** agents improved the atrophic changes and permeability in the ileum,with restoration of tight junction proteins(TJPs)

关键词： Liver fibrosis Intestinal permeability Alcoholic liver disease Lipopolysaccharide Toll-like receptor Tight junction protein

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Serum angiotensin-converting enzyme level for evaluating significant fibrosis in chronic hepatitis B

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World Journal of Gastroenterology 2017年第36期23卷 6705-6714页

作者： Ryuichi Noguchi Kosuke Kaji tadashi namisaki Kei Moriya Mitsuteru Kitade Kosuke Takeda Hideto Kawaratani Yasushi Okura Yosuke Aihara Masanori Furukawa Akira Mitoro Hitoshi Yoshiji Third Department of Internal Medicine Nara Medical University

AIM To evaluate the diagnostic performance of angiotensinconverting enzyme(ACE)on significant liver fibrosis in patients with chronic hepatitis B(CHB). METHODS In total,100 patients with CHB who underwent liver biopsy in our hospital were enrolled,and 70 patients except for 30 patients with hypertension,fatty liver or habitual alcoholic consumption were *** compared histological liver fibrosis and serum ACE levels and evaluated the predictive potential to diagnose significant liver fibrosis by comparison with several biochemical marker-based indexes such as the aspartate aminotransferase(AST)-to-platelet ratio index(APRI),the fibrosis index based on four factors(FIB-4),the Mac-2 binding protein glycosylation isomer(M2BPGi)level and the number of platelets(Plt). RESULTS Serum ACE levels showed moderately positive correlation with liver fibrotic stages(R2=0.181).Patients with significant,advanced fibrosis and cirrhosis(F2-4)had significantly higher serum ACE levels than those with early-stage fibrosis and cirrhosis(F0-1).For significant fibrosis(≥F2),the 12.8 U/L cut-off value of ACE showed 91.7%sensitivity and 75.0%*** receiver-operating characteristic(ROC)curves analysis revealed that the area under the curve(AUC)value of ACE was 0.871,which was higher than that of APRI,FIB-4,M2BPGi and Plt. CONCLUSION The serum ACE level could be a novel noninvasive,easy,accurate,and inexpensive marker of significant fibrosis stage in patients with CHB.

关键词： Angiotensin-converting enzyme Hepatitis B virus Liver fibrosis Noninvasive fibrosis marker Aspartate aminotransferase-to-platelet ratio index Fibrosis index based on four factors Mac-2 binding protein glycosylation isomer

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Acylcarnitine: Useful biomarker for early diagnosis of hepatocellular carcinoma in non-steatohepatitis patients

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World Journal of Gastrointestinal Oncology 2019年第10期11卷 887-897页

作者： Hiroaki Takaya tadashi namisaki Mitsuteru Kitade Naotaka Shimozato Kosuke Kaji Yuki Tsuji Keisuke Nakanishi Ryuichi Noguchi Yukihisa Fujinaga Yasuhiko Sawada Soichiro Saikawa Shinya Sato Hideto Kawaratani Kei Moriya Takemi Akahane Hitoshi Yoshiji Third Department of Internal Medicine Nara Medical University

BACKGROUND Early diagnosis of hepatocellular carcinoma(HCC)is necessary to improve the prognosis of ***,the currently available tumor biomarkers are insufficient for the early detection of *** is essential in fatty acid metabolic pathways.A recent study reported that a high level of acylcarnitine may serve as a useful biomarker for the early diagnosis of HCC in steatohepatitis(SH)*** contrast,another study reported that the level of acetylcarnitine(AC2)-one of the acylcarnitine species-in non-SH patients with HCC was decreased vs that reported in those without *** To investigate the usefulness of acylcarnitine as a biomarker for the early diagnosis of HCC in non-SH *** Thirty-three non-SH patients(14 with HCC and 19 without HCC)were enrolled in this *** samples were obtained from patients at the time of *** levels of acylcarnitine and AC2 in the serum were determined through tandem mass *** levels of vascular endothelial growth factor(VEGF)and VEGF receptor 2(VEGFR-2)were determined by enzymelinked immunosorbent *** and multivariate analyses were used to determine early diagnostic factors of *** The level of acylcarnitine was significantly lower in non-SH patients with HCC vs those without HCC(P<0.05).In contrast,the level of lens culinaris agglutininreactive fraction ofα-fetoprotein(AFP)-AFP-L3%-was significantly higher in non-SH patients with HCC vs those without HCC(P<0.05).However,the levels of total carnitine,free carnitine,AFP,des-γ-carboxy prothrombin,VEGF,and VEGFR-2 were not different between patients with and without *** multivariate analysis showed that a low level of acylcarnitine was the only independent factor for the early diagnosis of *** patients with a low level of AC2 had a significantly higher level of VEGF vs those with a high level of AC2(P<0.05).CONCLUSION The metabolic pathways of fatty acids may differ between SH HCC and non-SH HCC

关键词： Acylcarnitine Acetylcarnitine Biomarker Hepatocellular carcinoma Angiogenesis Carnitine palmitoyltransferase 1 Oxidative stress

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Association between ADAMTS13 activity-VWF antigen imbalance and the therapeutic effect of HAIC in patients with hepatocellular carcinoma

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World Journal of Gastroenterology 2020年第45期26卷 7232-7241页

作者： Hiroaki Takaya tadashi namisaki Kei Moriya Naotaka Shimozato Kosuke Kaji Hiroyuki Ogawa Koji Ishida Yuki Tsuji Daisuke Kaya Hirotestu Takagi Yukihisa Fujinaga Norihisa Nishimura Yasuhiko Sawada Hideto Kawaratani Takemi Akahane Masanori Matsumoto Hitoshi Yoshiji Department of Gastroenterology Nara Medical UniversityKashiharaNara 634-8522Japan Department of Blood Transfusion Medicine Nara Medical UniversityKashiharaNara 634-8522Japan

BACKGROUND Prediction of HAIC treatment response is important for improving the prognosis in patients with hepatocellular carcinoma(HCC).The progression of HCC is related to hypercoagulability and *** is known that ADAMTS13 and von Willebrand factor(VWF)are related to *** addition,previous study reported that the association between ADAMTS13 and VWF,and angiogenesis via vascular endothelial growth factor(VEGF).Recently,ADAMTS13 and VWF have been associated with the prognosis in patients with various kinds of cancer undergoing *** To investigate whether ADAMTS13 and VWF become useful biomarkers of treatment response in HCC patients before the initiation of HAIC *** Seventy-two patients were enrolled in this ***13 activity(ADAMTS13:AC),VWF antigen(VWF:Ag)and VEGF levels were determined via enzyme-linked immunosorbent *** and multivariable analyses were performed to determine the predictive factors of treatment response in patients with HCC undergoing HAIC *** ADAMTS13:AC levels in HCC patients with stable disease(SD)+partial response(PR)of HAIC treatment were significantly higher than those with progressive disease(PD)(P2.7)had higher VEGF levels than those with low ratio(≤2.7).Multivariable analysis revealed that VWF:Ag/ADAMTS13:AC ratio was a predictive factor of HAIC treatment *** VWF:Ag/ADAMTS13:AC ratio may become a useful biomarker of treatment response in HCC patients before the initiation of HAIC treatment.

关键词： ADAMTS13 Von Willebrand factor Vascular endothelial growth factor Biomarkers Hepatocellular carcinoma HAIC

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Plasma copeptin concentration is a predictor of tolvaptan efficacy in patients with hepatic ascites

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Portal Hypertension & Cirrhosis 2023年第3期2卷 109-114页

作者： Fumimasa Tomooka Kei Moriya Takahiro Kubo Akihiko Shibamoto Jyunya Suzuki Satoshi Iwai Soichi Takeda Yuki Fujimoto Masahide Enomoto Koji Murata Yuki Tsuji Yukihisa Fujinaga Koh Kitagawa Norihisa Nishimura Hiroaki Takaya Kosuke Kaji Hideto Kawaratani tadashi namisaki Takemi Akahane Akira Mitoro Hitoshi Yoshiji Department of Gastroenterology and Hepatology Nara Medical UniversityKashiharaJapan Department of Gastroenterology Nara Prefectural General Medical CenterShichijo-NishimachiJapan

Aims:No solid evidence-based opinion was raised regarding predictors of the degree of ascites reduction with *** retrospective cohort study aimed to examine whether serum copeptin concentration is a useful predictor of ***:The study population consisted of 80 patients with liver cirrhosis treated with tolvaptan for hepatic ascites effusions at Nara Medical University Hospital from May 2014 to December ***-three patients who lost>1.5 kg of body weight in the first week after starting tolvaptan were classified as good responders and the remaining 37 as poor *** laboratory parameters were measured immediately before the start of tolvaptan therapy to examine factors associated with predicting its ***:In the univariate analysis,no significant differences with respect to age(67.6 vs.69.8 years,p>0.05),sex,body mass index(24.8 vs.23.7 kg/m^(2),p>0.05),Child-Pugh score(9.4 vs.9.7,p>0.05),and Model for End-stage Liver Disease score(11 vs.12,p>0.05)were found between the two ***,aspartate transferase and alanine transaminase(ALT)levels were significantly lower in the good response group(52.9±56.3 vs.68.8±50.7 U/L,p<0.05;26.2±30.6 vs.40.5±33.5 U/L,p<0.01),whereas serum copeptin and serum sodium concentrations were significantly higher(57.1±15.0 vs.45.8±16.0 pg/mL,p<0.01;136.3±3.4 vs.133.8±5.8 mEq/L,p<0.05).In the multivariate analysis,serum copeptin concentration and ALT were statistically significant factors(p<0.01,p<0.05).Regression analysis of the association between the tolvaptan efficacy for refractory ascites and pretreatment serum copeptin concentration showed that a copeptin concentration cutoff of 45.9 pg/mL could predict treatment efficacy with a sensitivity,specificity,and area under the curve of 76.7%,59.5%,and 0.71%,***:Serum copeptin concentration may be a predictor of tolvaptan efficacy for refractory ascites effusion in Japanese patients with liver cirrhosis.

关键词： ascites copeptin decompensated liver cirrhosis diuretics tolvaptan

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DNA methylation of angiotensin Ⅱ receptor gene in nonalcoholic steatohepatitis-related liver fibrosis

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World Journal of Hepatology 2016年第28期8卷 1194-1199页

作者： Kiyoshi Asada Yosuke Aihara Hiroaki Takaya Ryuichi Noguchi tadashi namisaki Kei Moriya Masakazu Uejima Mitsuteru Kitade Tsuyoshi Mashitani Kosuke Takeda Hideto Kawaratani Yasushi Okura Kosuke Kaji Akitoshi Douhara Yasuhiko Sawada Norihisa Nishimura Kenichiro Seki Akira Mitoro Junichi Yamao Hitoshi Yoshiji Third Department of Internal Medicine Nara Medical University

AIM To clarify whether Agtr1 a methylation is involved in the development of nonalcoholic steatohepatitis(NASH)-related liver fibrosis in adult *** A choline-deficient amino acid(CDAA) diet model was employed for methylation analysis of NASH-related liver ***1 a methylation levels were measured in the livers of CDAA- and control choline-sufficient amino acid(CSAA)-fed rats for 8 and 12 wk using quantitative methylation-specific *** stellate cells(HSCs) were isolated by collagenase digestion of the liver,followed by centrifugation of the crude cell suspension through a density ***1 a methylation and its gene expression were also analyzed during the activation of *** The mean levels of Agtr1 a methylation in the livers of CDAA-fed rats(11.5% and 18.6% at 8 and 12 wk,respectively) tended to be higher(P = 0.06 and 0.09,respectively) than those in the livers of CSAA-fed rats(2.1% and 5.3% at 8 and 12 wk,respectively).Agtr1 a was not methylated at all in quiescent HSCs,but was clearly methylated in activated HSCs(13.8%,P < 0.01).Interestingly,although Agtr1 a was hypermethylated,the Agtr1 a m RNA level increased up to 2.2-fold(P < 0.05) in activated HSCs compared with that in quiescent HSCs,suggesting that Agtr1 a methylation did not silence its expression but instead had the potential to upregulate its *** findings indicate that Agtr1 a methylation and its upregulation of gene expression are associated with the development of NASH-related liver *** This is the first study to show that DNA methylation is potential y involved in the regulation of a renin-angiotensin system-related gene expression during liver fibrosis.

关键词： Epigenetics DNA methylation Angiotensin Ⅱ receptor Liver fibrosis Nonalcoholic steatohepatitis

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