Pathogenesis ofmetabolic syndrome and non-alcoholic steatohepatitis

• Project/Area Number: 23659470
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Metabolomics
• Research Institution: Okayama University
• Principal Investigator: WADA Jun 岡山大学, 大学院・医歯薬学総合研究科, 准教授 (30294408)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2012: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 脂肪肝炎 / Pemt / メタボリックシンドローム / ホスファチジルコリン / ホスファチジルエタノラミン / 脂肪肝 / インスリン抵抗性 / 小胞体ストレス / 肥満 / DNAメチル化 / phosphatidylcholine / phosphatidylethanolamine / PEMTノックアウトマウス

Research Abstract

We identified mRNA expression of Phosphatidylethanolamine N-methyltransferase (Pemt) was up-regulated in the liver tissue of obese mice. Body weight and accumulation of adipose tissues were prominently reduced in high fat-high sucrose induced obese Pemtknockout mice and insulin resistance was significantly improved. However, these animals developed severe steatohepatitis and ultimately liver cirrhosis and adenomas. The reduction of Pemt activity is involved in the development of non-alcoholic steatohepatitis.

Research Products

• [Journal Article] Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease (2013)
  • Author(s): Kurose Y, Wada J, Kanzaki M, Teshigawara S, Nakatsuka A, Murakami K, Inoue K, Terami T, Katayama A, Watanabe M, Higushi C, Eguchi J, Miyatake N, Makino H.
  • Journal Title: BMC Nephrol Volume: 14 Pages: 23-23
  • NAID: 120005324795
  • Peer Reviewed
• [Journal Article] Vaspin inhibits apoptosis of endothelial cells as a ligand for cell-surface GRP78/VDAC complex. (2013)
  • Author(s): Nakatsuka A, Wada J, Iseda I, Teshigawara S, Higashio K, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Hida K, Eguchi J, Ogawa D, Matsuki Y, Hiramatsu R, Tagita H, Kakuta S, Iwakura Y, Makino H.
  • Journal Title: Circ Res Volume: 112(5) Pages: 771-80
  • Peer Reviewed
• [Journal Article] Telmisartan attenuates diabetic nephropathy by suppressing ixidative stress in db/db mice. (2013)
  • Author(s): Sato-Horiguchi C, Ogawa D, Wada J, Tachibana H, Kodera R, Eguchi J, Nakatsuka A, Terami N, Shikata K, Makino H.
  • Journal Title: Nephron Exp Nephrol Volume: 121(3-4)
  • Peer Reviewed
• [Journal Article] The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO). (2013)
  • Author(s): Murakami K, Wada J, Ogawa D, Horiguchi CS, Miyoshi T, Sasaki M, Uchida HA,Nakamura Y, Makino H.
  • Journal Title: Diab Vasc Dis Res Volume: 10(1) Pages: 93-6
  • Peer Reviewed
• [Journal Article] The effects of telmisartan treatment on the abdominal fat depot in patients with metabolic syndrome and essential hypertension: Abdominal fat Depot Intervention Program of Okayama (ADIPO). (2013)
  • Author(s): Murakami K
  • Journal Title: Diab Vasc Dis Res Volume: 10(1) Issue: 1 Pages: 93-96
  • DOI: 10.1177/1479164112444640
  • Peer Reviewed
• [Journal Article] Telmisartan attenuates diabetic nephropathy by suppressing ixidative stress in db/db mice. (2013)
  • Author(s): Sato-Horiguchi C
  • Journal Title: Nephron Exp Nephrol Volume: 121(3-4) Issue: 3-4 Pages: 97-108
  • DOI: 10.1159/000343102
  • Peer Reviewed
• [Journal Article] Vaspin inhibits apoptosis of endothelial cells as a ligand for cell-surface GRP78/VDAC complex. (2013)
  • Author(s): Nakatsuka A
  • Journal Title: Cir Res Volume: 112(5) Issue: 5 Pages: 771-780
  • DOI: 10.1161/circresaha.111.300049
  • Peer Reviewed
• [Journal Article] Serum galectin-9 levels are elevated in the patients with type 2 diabetes and chronic kidney disease. (2013)
  • Author(s): Kurose Y
  • Journal Title: BMC Nephrol Volume: 14 Issue: 1 Pages: 23-23
  • DOI: 10.1186/1471-2369-14-23
  • Peer Reviewed
• [Journal Article] The serum vaspin levels are reduced in Japanese chronic hemodialysis patients. (2012)
  • Author(s): Inoue J, Wada J, Teshigawara S, Hida K, Nakatsuka A, Takatori U, Kojo S, Akagi S, Nakao K, Miyatake N, McDonald JF, Makino H.
  • Journal Title: BMC Nephrol Volume: 13(1) Pages: 163-163
  • NAID: 120005315579
  • Peer Reviewed
• [Journal Article] Activation of liver x receptor inhibits osteopontin and ameliorates diabetic nephropathy (2012)
  • Author(s): Tachibana H, Ogawa D, Matsushita Y, Bruemmer D, Wada J, Teshigawara S, Eguchi J, Sato-Horiguchi C, Uchida HA, Shikata K, Makino H.
  • Journal Title: J Am Soc Nephrol Volume: 23(11) Pages: 1835-46
  • Peer Reviewed
• [Journal Article] Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex. (2012)
  • Author(s): Nakatsuka A, Wada J, Iseda I, Teshigawara S, Higashio K, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Hida K, Eguchi J, Horiguchi CS, Ogawa D, Matsuki Y, Hiramatsu R, Yagita H, Kakuta S, Iwakura Y, Makino H.
  • Journal Title: Diabetes Volume: 61(11) Pages: 2823-32
  • NAID: 120005300245
  • Peer Reviewed
• [Journal Article] The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome: a randomized controlled trial. (2012)
  • Author(s): Kanzaki M, Wada J, Kikumoto Y, Akagi S, Nakao K, Sugiyama H, Makino H.
  • Journal Title: Int J Nephrol Renovasc Dis Volume: 5 Pages: 91-6
  • Peer Reviewed
• [Journal Article] Hydrogen-rich water prevents progression of non-alcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice (2012)
  • Author(s): Kawai D, Takaki A, Nakatsuka A, Wada J, Tamaki N, Yasunaka T, Koike K, Tsuzaki R, Matsumoto K, Miyake Y, Shiraha H, Morita M, Makino H, Yamamoto K.
  • Journal Title: Hepatology Volume: 56(3) Pages: 912-21
  • Peer Reviewed
• [Journal Article] Serum vaspin concentrations are closely related to insulin resistance and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population (2012)
  • Author(s): Teshigawara S, Wada J, Hida K, Nakatsuka A, Eguchi J, Murakami K, Kanzaki M, Inoe K, Terami T, Katayama A, Iseda I, Matsushita Y, Miyatake N, McDonald JF, Hotta K, Makino H.
  • Journal Title: J Clin Endocrinol Metab Volume: 97(7)
  • NAID: 120005232486
  • Peer Reviewed
• [Journal Article] Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes (2012)
  • Author(s): Kanzaki M, Wada J, Sugiyama K, Nakatsuka A, Teshigawara S, Murakami K, Inoue K, Terami T, Katayama A, Eguchi J, Akiba H, Yagita H, Makino H.
  • Journal Title: Endocrinology Volume: 153(2) Pages: 612-20
  • Peer Reviewed
• [Journal Article] Impact of circulating vaspin levels on metabolic variables in elderly twins. (2012)
  • Author(s): Hida K, Poulsen P, Teshigawara S, Nilsson E, Friedrichsen M, Ribel-Madsen R, Grunnet L, Lund SS, Wada J, Vaag A.
  • Journal Title: Diabetologia Volume: 55(2) Pages: 530-2
  • Peer Reviewed
• [Journal Article] RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21Cip1pathway in adipocytes. (2012)
  • Author(s): Nakatsuka A, Wada J, Hida K, Hida A, Eguchi J, Teshigawara S, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Ogawa D, Kagechika H, Makino H.
  • Journal Title: J Pathol Volume: 226(5) Pages: 784-95
  • NAID: 130004505771
  • Peer Reviewed
• [Journal Article] Impact of circulating vaspin levels on metabolic variables in elderly twins. (2012)
  • Author(s): Hida K
  • Journal Title: Diabetologia Volume: 55(2) Issue: 2 Pages: 530-532
  • DOI: 10.1007/s00125-011-2385-0
  • Peer Reviewed
• [Journal Article] Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. (2012)
  • Author(s): Kanzaki M
  • Journal Title: Endocrinology Volume: 153(2) Issue: 2 Pages: 612-620
  • DOI: 10.1210/en.2011-1579
  • Peer Reviewed
• [Journal Article] Serum vaspin concentrations are closely related to insulin resistance and rs77060950 at SERPINA12 genetically defines distinct group with higher serum levels in Japanese population. (2012)
  • Author(s): Teshigawara S
  • Journal Title: J Clin Endocrinol Metab Volume: 97(7) Issue: 7 Pages: E1202-E1207
  • DOI: 10.1210/jc.2011-3297
  • Peer Reviewed
• [Journal Article] Hydrogen-rich water prevents progression of non-alcoholic steatohepatitis and accompanying hepatocarcinogenesis in mice (2012)
  • Author(s): Kawai D, Takaki A, Nakatsuka A, Wada J, Tamaki N, Yasunaka T, Koike K, Tsuzaki R, Matsumoto K, Miyake Y, Shiraha H, Morita M, Makino H, Yamamoto K
  • Journal Title: Hepatology Volume: 56(3) Issue: 3 Pages: 912-921
  • DOI: 10.1002/hep.25782
  • Peer Reviewed
• [Journal Article] The therapeutic potential of synthetic human atrial natriuretic peptide in nephrotic syndrome : a randomized controlled trial (2012)
  • Author(s): Kanzaki M, Wada J, Kikumoto Y, Akagi S, Nakao K, Sugiyama H, Makino H
  • Journal Title: Int J Nephrol Renovasc Dis Volume: 5 Pages: 91-96
  • DOI: 10.2147/ijnrd.s32191
  • Peer Reviewed
• [Journal Article] Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex (2012)
  • Author(s): Nakatsuka A, Wada J, Iseda I, Teshigawara S, Higashio K, Murakami K, Kanzaki M, Inoue K, Terami T, Katayama A, Hida K, Eguchi J, Horiguchi CS, Ogawa D, Matsuki Y, Hiramatsu R, Yagita H, Kakuta S, Iwakura Y, Makino H
  • Journal Title: Diabetes Volume: 61(11) Issue: 11 Pages: 2823-2832
  • DOI: 10.2337/db12-0232
  • NAID: 120005300245
  • Peer Reviewed
• [Journal Article] Activation of liver x receptor inhibits osteopontin and ameliorates diabetic nephropathy. (2012)
  • Author(s): Tachibana H
  • Journal Title: J Am Soc Nephrol Volume: 23(11) Issue: 11 Pages: 1835-1846
  • DOI: 10.1681/asn.2012010022
  • Peer Reviewed
• [Journal Article] The serum vaspin levels are reduced in Japanese chronic hemodialysis patients. (2012)
  • Author(s): Inoue J
  • Journal Title: BMC Nephrol Volume: 13(1) Issue: 1 Pages: 163-163
  • DOI: 10.1186/1471-2369-13-163
  • Peer Reviewed
• [Journal Article] RXR antagonism induces G0/G1 cell cycle arrest and ameliorates obesity by up-regulating the p53-p21Cip1 pathway in adipocytes (2012)
  • Author(s): Nakatsuka A, et al
  • Journal Title: J Pathol Volume: 226(5) Issue: 5 Pages: 784-795
  • DOI: 10.1002/path.3001
  • Peer Reviewed
• [Journal Article] Impact of circulating vaspin levels on metabolic in elderly twins. (2012)
  • Author(s): Hida K et al.
  • Journal Title: Diabetologia Volume: 55(2) Pages: 530-532
  • Peer Reviewed
• [Journal Article] Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes. (2012)
  • Author(s): Kanzaki M et al.
  • Journal Title: Endocrinology Volume: 51(6) Pages: 619-623
  • Peer Reviewed
• [Journal Article] Ogawa D, Asanuma M, Miyazaki I, Tachibana H, Wada J, Sogawa N, Sugaya T, Kitamura S, Maeshima Y, Shikata K, Makino H. (2011)
  • Author(s): Ogawa D, Asanuma M, Miyazaki I, Tachibana H, Wada J, Sogawa N, Sugaya T, Kitamura S, Maeshima Y, Shikata K, Makino H.
  • Journal Title: Exp Diabetes Res 2011 Pages: 534872-534872
  • Peer Reviewed
• [Journal Article] Icodextrin increases technique survival rate in peritoneal dialysis patients with diabetic nephropathy by improving body fluid management: a randomized controlled trial (2011)
  • Author(s): Takatori Y, Akagi S, Sugiyama H, Inoue J, Kojo S, Morinaga H, Nakao K, Wada J, Makino H.
  • Journal Title: Clin J Am Soc Nephrol Volume: 6(6) Pages: 1337-44
  • Peer Reviewed
• [Journal Article] Activation of Peroxisome Proliferator-Activated Receptor δInhibits Streptozotocin-Induced Diabetic Nephropathy Through Anti-Inflammatory Mechanisms in Mice (2011)
  • Author(s): Matsushita Y, Ogawa D, Wada J, Yamamoto N, Shikata K, Sato C, Tachibana H, Toyota N, Makino H.
  • Journal Title: Diabetes Volume: 60(3) Pages: 960-8
  • Peer Reviewed
• [Journal Article] P-selectin glycoprotein ligand-1 deficiency is protective against obesity-related insulin resistance (2011)
  • Author(s): Sato C, Shikata K, Hirota D, Sasaki M, Nishishita S, Miyamoto S, Kodera R, Ogawa D, Tone A, Kataoka HU, Wada J, Kajitani N, Makino H.
  • Journal Title: Diabetes Volume: 60(1) Pages: 189-99
  • Peer Reviewed
• [Journal Article] Icodextrin increases technique survival rate in peritoneal dialysis patients with diabetic nephropathy by improving body fluid management: a randomized controlled trial. (2011)
  • Author(s): Takatori Y et al.
  • Journal Title: Clin J Am Soc Nephrol Volume: 6(6) Pages: 1337-1344
  • Peer Reviewed
• [Presentation] Identification of transmembrnane proteins expressed in adipocytes under obese-state and the roles of soluble forms in fat accumulation. (2012)
  • Author(s): Wada J
  • Organizer: International Symposium for the Study of Obesity "Translational Science and Epidemiology on Adipomedicine; From Lipodystrophy to Obesity"
  • Place of Presentation: Shiran Kaikan of Kyoto University, Kyoto
  • Year and Date: 2012-10-13
• [Presentation] PEMT deficiency protects from obesity and insulin resistance, but induces severe steathepatitis. シンポジウム3:慢性炎症とインスリン抵抗性 (2012)
  • Author(s): 和田淳
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2012-05-17
• [Presentation] コレクトリンとprimary ciliaシンポジウムCiliopathies; Ciliaは細胞のconductor (2011)
  • Author(s): 和田淳
  • Organizer: 第54回日本腎臓病学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2011-06-15
• [Presentation] シンポジウム Ciliopathies; Ciliaは細胞のconductor コレクトリンとprimary cilia (2011)
  • Author(s): 和田淳
  • Organizer: 第54回日本腎臓病学会学術集会(招待講演)
  • Place of Presentation: 横浜
• [Presentation] Identification of transmembrnane proteins expressed in adipocytes under obese-state and the roles of soluble forms in fat accumulation.
  • Author(s): Wada J
  • Organizer: International Symposium for the Study of Obesity “Translational Science and Epidemiology on Adipomedicine; From Lipodystrophy to Obesity”
  • Place of Presentation: Shiran Kaikan of Kyoto University, Kyoto
  • Invited
• [Presentation] PEMT deficiency protects from obesity and insulin resistance, but induces severe steathepatitis.
  • Author(s): 和田淳
  • Organizer: 第55回日本糖尿病学会年次学術集会
  • Place of Presentation: 横浜
  • Invited
• [Book] 尿検査の意義-蛋白尿-糖尿病×CKD診療ガイド (2012)
  • Author(s): 和田淳
  • Publisher: 南山堂
• [Book] 糖尿病×CKD診療ガイド (2012)
  • Author(s): 和田淳
  • Total Pages: 197
  • Publisher: 南山堂