The role and crosstalk between nuclear receptors PXR and CAR on the pathogenesis of non-alcoholic steatohepatitis.

• Project/Area Number: 20590759
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Gunma University
• Principal Investigator: KAKIZAKI Satoru 群馬大学, 医学部, 助教 (80344935)
• Co-Investigator(Renkei-kenkyūsha): YOSHINARI Koichi 東北大学, 薬学研究科(研究院), 准教授 (60343399)
• Project Period (FY): 2008 – 2011
• Project Status: Completed (Fiscal Year 2011)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2011: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2010: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 非アルコール性脂肪性肝炎 / 核内レセプター / CAR / PXR / Cytochrome P450 / 肝線維化 / Ctochrome P450

Research Abstract

The roles and crosstalk between nuclear receptors PXR and CAR on the pathogenesis of non-alcoholic steatohepatitis (NASH) were evaluated in this study. CAR accelerated the production of reactive oxygen species (ROS) and worsened the liver injury and fibrosis in the NASH model using methionine-and choline-deficient diet. There were no differences in NASH between PXR knockout and wild-type mice. CAR play a role in the hepatocarcinogenesis of the murine NASH model via the upregulation of cell proliferation.

Research Products

• [Journal Article] Azelnidipine is a calcium blocker that attenuates liver fibrosis and may increase antioxidant defence (2012)
  • Author(s): Ohyama T, Sato K, Kishimoto K, Yamazaki Y, Horiguchi N, Ichikawa T, Kakizaki S, et al.
  • Journal Title: Br J Pharmacol Volume: 165 Issue: 4b Pages: 1173-87
  • DOI: 10.1111/j.1476-5381.2011.01599.x
  • Peer Reviewed
• [Journal Article] Constitutive active/androstane receptor promotes hepato-carcinogenesis in a mouse model of non-alcoholic steatohepatitis (2011)
  • Author(s): Takizawa D, Kakizaki S, et al
  • Journal Title: Carcinogenesis Volume: 32 Pages: 83-576
  • Peer Reviewed
• [Journal Article] Nuclear Receptors CAR and PXR ; therapeutic targets for cholestatic liver disease (2011)
  • Author(s): Kakizaki S, et al
  • Journal Title: Front Biosci Volume: 17 Pages: 2988-3003
  • Peer Reviewed
• [Journal Article] Nuclear receptor CAR-regulated expression of the FAM84A gene during the development of mouse liver tumors (2011)
  • Author(s): Kamino H, Yamazaki Y, Saito K, Takizawa D, Kakizaki S, et al
  • Journal Title: Int J Oncol Volume: 38 Pages: 20-1511
  • Peer Reviewed
• [Journal Article] Nuclear receptors CAR and PXR ; therapeutic targets for cholestatic liver disease (2011)
  • Author(s): Kakizaki S, et al.
  • Journal Title: Front Biosci Volume: 17 Issue: 1 Pages: 2988-3005
  • DOI: 10.2741/3893
  • Peer Reviewed
• [Journal Article] Constitutive active/androstane receptor promotes hepatocarcinogenesis in amouse model of non-alcoholic steatohepatitis (2011)
  • Author(s): Takizawa D, Kakizaki S, et al.
  • Journal Title: Carcinogenesis Volume: 32 Issue: 4 Pages: 576-83
  • DOI: 10.1093/carcin/bgq277
  • Peer Reviewed
• [Journal Article] Nuclear receptor CAR-regulated expression of the FAM84A gene during the development of mouse liver tumors (2011)
  • Author(s): Kamino H, Yamazaki Y, Saito K, Takizawa D, Kakizaki S, et al.
  • Journal Title: Int J Oncol Volume: 38 Pages: 1511-20
  • DOI: 10.3892/ijo.2011.980
  • Peer Reviewed
• [Journal Article] Transforming growth factor-a attenuates hepatic fibrosis : possible involvement of matrix metalloproteinase-1 (2011)
  • Author(s): Ohyama T, Yamazaki Y, Sato K, Horiguchi N, Ichikawa T, Kakizaki S, et al.
  • Journal Title: Liver Int Volume: 31 Issue: 4 Pages: 572-84
  • DOI: 10.1111/j.1478-3231.2011.02475.x
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor overexpression ameliorates liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis (2011)
  • Author(s): Tojima H, Kakizaki S, et al.
  • Journal Title: Hepatol Int Volume: (印刷中) Issue: 3 Pages: 620-630
  • DOI: 10.1007/s12072-011-9301-z
  • Peer Reviewed
• [Journal Article] Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis. (2011)
  • Author(s): Takizawa D, Kakizaki S, et al.
  • Journal Title: Carcinogenesis. in press
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor overexpression ameliorates liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. (2011)
  • Author(s): Tojima H, Kakizaki S, et al.
  • Journal Title: Hepatol Int. in press
  • Peer Reviewed
• [Journal Article] Nuclear receptor CAR-regulated expression of the FAM84A gene during the development of mouse liver tumors. (2011)
  • Author(s): Kamino H, Yamazaki Y, Saito K, Takizawa D, Kakizaki S, et al.
  • Journal Title: Int J Oncol. in press
  • Peer Reviewed
• [Journal Article] Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis. (2011)
  • Author(s): Takizawa D, Kakizaki S, et al.
  • Journal Title: Carcinogenesis Volume: in press
  • Peer Reviewed
• [Journal Article] Nuclear receptor CAR-regulated expression of the FAM84A gei during the development of mouse liver tumors. (2011)
  • Author(s): Kamino H, Yamazaki Y, Saito K, Takizawa D, Kakizaki S, et al.
  • Journal Title: Int J Oncol. Volume: in press
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor overexpression ameliorates liver inflam mation and fibrosis in a mouse model of nonalcoholic steatohepa titis. (2011)
  • Author(s): Tojima H, Kakizaki S, et al.
  • Journal Title: Hepatol Int. Volume: in press
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitors induce cytochrome P450 2B by activating nuclear receptor constitutive and rostane receptor (2010)
  • Author(s): Takizawa D, Kakizaki S, et al
  • Journal Title: Drug Metab Dispos. Volume: 38 Pages: 8-1493
  • Peer Reviewed
• [Journal Article] Fucosylated fraction of alpha-fetoprotein as a predictor of prognosis in patients with hepatocellular carcinoma after curative treatment (2010)
  • Author(s): Tamura Y, Igarashi M, Suda T, Wakai T, Umemura T, Tanaka E, Kakizaki S, et al
  • Journal Title: Dig Dis Sci. Volume: 55 Pages: 101-2095
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitors induce cytochrome P450 2B by activating nuclear receptor constitutive androstane receptor. (2010)
  • Author(s): Takizawa D, Kakizaki S, et al.
  • Journal Title: Drug Metab Dispos. 38 Pages: 1493-1498
  • Peer Reviewed
• [Journal Article] Histone deacetylase inhibitors induce cytochrome P450 2B by activating nuclear receptor constitutive androstane receptor. (2010)
  • Author(s): Takizawa D, Kakizaki S, et al.
  • Journal Title: Drug Metab Dispos. Volume: 38 Pages: 1493-1498
  • Peer Reviewed
• [Journal Article] Xenobiotic-sensing nuclear receptors CAR and PXR as drug targets in cholestatic liver disease (2009)
  • Author(s): Kakizaki S, et al
  • Journal Title: Curr Drug Targets Volume: 10 Pages: 1156-1163
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor protects against Fas-mediated liver apoptosis in transgenic mice (2009)
  • Author(s): Suzuki H, Toyoda M, Horiguchi N, Kakizaki S, et al
  • Journal Title: Liver Int Volume: 29 Pages: 8-1562
  • Peer Reviewed
• [Journal Article] Xenobiotic-sensing nuclear receptors CAR and PXR as drug targets in cholestatic liver disease. (2009)
  • Author(s): Kakizaki S, et al.
  • Journal Title: Curr Drug Targets. 10 Pages: 1156-1163
  • Peer Reviewed
• [Journal Article] Hepatocyte growth factor protects against Fas-mediated liver apoptosis in transgenic mice. (2009)
  • Author(s): Suzuki H, Toyoda M, Horiguchi N, Kakizaki S, et al.
  • Journal Title: Liver Int. 29 Pages: 1562-1568
  • Peer Reviewed
• [Journal Article] Xenobiotic-Sensing Nuclear Receptors CAR and PXR as Drug Targets in Cholestatic Liver Disease. (2009)
  • Author(s): Kakizaki S, et al.
  • Journal Title: Curr Drug Targets. 10 Pages: 1184-93
  • Peer Reviewed
• [Journal Article] New insights on the xenobiotic-sensing nuclear receptors in liver diseases-CAR and PXR- (2008)
  • Author(s): Kakizaki S, et al
  • Journal Title: Curr Drug Metab Volume: 9 Pages: 21-614
  • Peer Reviewed
• [Journal Article] Interstrain differences in susceptibility to non-alcoholic steatohepatitis (2008)
  • Author(s): Yamazaki Y, Kakizaki S, et al
  • Journal Title: J Gastroenterol Hepatol Volume: 23 Pages: 82-276
  • Peer Reviewed
• [Journal Article] Transcriptional regulation of human UGT1A1 gene expression through distal and proximal promoter motifs : implication of defects in the UGT1A1 gene promoter (2008)
  • Author(s): Sugatani J, Mizushima K, Osabe M, Yamakawa K, Kakizaki S, et al
  • Journal Title: Naunyn Schmiedebergs Arch Pharmacol. Volume: 377 Pages: 597-605
  • Peer Reviewed
• [Journal Article] Overexpression of NK2 promotes liver fibrosis in carbon tetrachloride-induced chronic liver injury (2008)
  • Author(s): Hagiwara S, Otsuka T, Yamazaki Y, Kosone T, Sohara N, Ichikawa T, Sar￥to K, Kakizaki S, et al
  • Journal Title: Liver Int Volume: 28 Pages: 31-126
  • Peer Reviewed
• [Journal Article] Non alcoholic fatty liver disease in Japanese patients with severe obesity who received laparoscopic Roux-en-Y gastric bypass surgery (LRYGB) in comparison to non-Japanese patients (2008)
  • Author(s): Kakizaki S, et al
  • Journal Title: J Gastroenterol. Volume: 43 Pages: 86-92
  • NAID: 10021267427
  • Peer Reviewed
• [Journal Article] Transforming growth factor-alpha accelerates hepatocyte repopulation after hepatocyte transplantation (2008)
  • Author(s): Kosone T, Takagi H, Horiguchi N, Kakizaki S, et al
  • Journal Title: J Gastroenterol Hepatol Volume: 23 Pages: 6-260
  • Peer Reviewed
• [Journal Article] New insights on the xenobiotic-sensing nuclear receptors in liver diseases--CAR and PXR--. (2008)
  • Author(s): Kakizaki S, et al.
  • Journal Title: Curr Drug Metab. 9 Pages: 614-621
  • Peer Reviewed
• [Journal Article] Nonalcoholic fatty liver disease in Japanese patients with severe obesity who received laparoscopic Roux-en-Y gastric bypass surgery(LRYGB)in comparison to non-Japanese patients. (2008)
  • Author(s): Kakizaki S, et al.
  • Journal Title: J Gastroenterol. 43 Pages: 86-92
  • NAID: 10021267427
  • Peer Reviewed
• [Journal Article] New insights on the xenobiotic-sensing nuclear receptors in liver diseases-CAR and PXR-. (2008)
  • Author(s): Kakizaki S, et al.
  • Journal Title: Curr Drug Metab. 9 Pages: 614-621
  • Peer Reviewed
• [Journal Article] Nonalcoholic fatty liver disease in Japanese patients with severe obesity who received laparoscopic Roux-en-Y gastric bypass surgery (LRYGRB) in comparison to non-Japanese patients. (2008)
  • Author(s): Kakizaki S, et al.
  • Journal Title: J Gastroenterol. 43 Pages: 86-92
  • Peer Reviewed
• [Journal Article] Interstrain differences in susceptibility to non-alcoholic steatohenatitis. (2008)
  • Author(s): Yamazaki Y, Kakizaki S, et al.
  • Journal Title: J Gastroenterol Hepatol. 23 Pages: 276-282
  • Peer Reviewed
• [Presentation] Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver (2011)
  • Author(s): Yamazaki Y, Kakizaki S, et al
  • Organizer: The Liver Meeting 2011(アメリカ肝臓学会)
  • Place of Presentation: アメリカ合衆国・サンフランシスコ・モスコーンウエスト国際会議場
  • Year and Date: 2011-11-06
• [Presentation] Nuclear receptor CAR (NR113) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver (2011)
  • Author(s): Yamazaki Y, Kakizaki S, et al.
  • Organizer: The Liver Meeting 2011(アメリカ肝臓学会)
  • Place of Presentation: アメリカ合衆国・サンフランシスコ・モスコーンウエスト国際会議場
  • Year and Date: 2011-11-06
• [Presentation] Constitutive active/androstane receptor promotes hepatocarcinogenesis in a mouse model of non-alcoholic steatohepatitis (2011)
  • Author(s): Takizawa D, Kakizaki S, et al
  • Organizer: DDW2011(アメリカ消化器病週間)
  • Place of Presentation: アメリカ合衆国・シカゴ・マコーミックプレース国際会議場
  • Year and Date: 2011-05-10
• [Presentation] Transforming growth factor-α attenuates hepatic fibrosis : possible involvement of matrix metalloproteinase-1 (2011)
  • Author(s): Ohyama T, Yamazaki Y, Sato K, Horiguchi N, Ichikawa T, Kakizaki S, et al
  • Organizer: DDW2011(アメリカ消化器病週間)
  • Place of Presentation: アメリカ合衆国・シカゴ・マコーミックプレース国際会議場
  • Year and Date: 2011-05-10
• [Presentation] Constitutive active/androstane receptor promotes hepatocarcinogenesis in amouse model of non-alcoholic steatohepatitis (2011)
  • Author(s): Takizawa D, Kakizaki S, et al.
  • Organizer: DDW 2011(アメリカ消化器病週間)
  • Place of Presentation: アメリカ合衆国・シカゴ・マコーミックプレース国際会議場
  • Year and Date: 2011-05-10
• [Presentation] Transforming growth factor-α attenuates hepatic fibrosis : possible involvement of matrix metalloproteinase-1 (2011)
  • Author(s): Ohyama T, Yamazaki Y, Sato K, Horiguchi N, Ichikawa T, Kakizaki S, et al.
  • Organizer: DDW 2011(アメリカ消化器病週間)
  • Place of Presentation: アメリカ合衆国・シカゴ・マコーミックプレース国際会議場
  • Year and Date: 2011-05-10
• [Presentation] HGF promotes DEN-induced hepatocarcinogenesis, but attenuates MCD-induced liver inflammation and fibrosis. (2010)
  • Author(s): Horiguchi N, Kakizaki S, et al.
  • Organizer: AASLD Liver meeting.
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2010-11-01
• [Presentation] Hepatocyte growth factor overexpression ameliorates liver inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis. (2010)
  • Author(s): Kakizaki S, et al.
  • Organizer: 18^<th> UEGW.
  • Place of Presentation: Barcelona, Spain
  • Year and Date: 2010-10-27
• [Presentation] Nuclear xenobiotic receptor CAR is essential for DDC to proliferate oval cells in mouse liver (2010)
  • Author(s): Yamazaki Y, Moore R, Kakizaki S, et al
  • Organizer: 18^<th> International Symposium on Microsomes and Drug Oxidations
  • Place of Presentation: 中国・北京
  • Year and Date: 2010-05-17
• [Presentation] Nuclear xenobiotic receptor CAR is essential for DDC to proliferate oval cells in mouse liver. (2010)
  • Author(s): Yamazaki Y, Moore R, Kakizaki S, et al.
  • Organizer: 18^<th> International Symposium on Microsomes and Drug Oxidations.
  • Place of Presentation: Beijing, China
  • Year and Date: 2010-05-17
• [Presentation] Nuclear xenobiotic receptor CAR is essential for DDC to proliferate oval cells in mouse liver. (2010)
  • Author(s): Yamazaki Y, Moore R, Kakizaki S, et al.
  • Organizer: 18^<th> International Symposium on Microsomes Drug Oxidations
  • Place of Presentation: Beijing, China
  • Year and Date: 2010-05-17
• [Presentation] Nonalcoholic fatty liver disease in Japanese patients with severe obesity who received laparoscopic Roux-en-Y gastric bypass surgery(LRYGB)in comparison to non-Japanese patients. (2008)
  • Author(s): Kakizaki S, et al.
  • Organizer: 109^<th> annual meeting of the AGA institute.
  • Place of Presentation: San Diego, CA, USA
  • Year and Date: 2008-05-19