肥満2型糖尿病モデルSDT fattyラットにおける非アルコール性脂肪肝炎発症の早期化の検討と各種薬剤の薬効評価

• Material Type: 博士論文
• Title: 肥満2型糖尿病モデルSDT fattyラットにおける非アルコール性脂肪肝炎発症の早期化の検討と各種薬剤の薬効評価
• Author/Editor: 鳥庭, 靖文
• Publication, Distribution, etc.: 新潟大学
• Publication Date: 2019-03-25
• Publication Date (W3CDTF): 2019-03-25
• Alternative Title: 肥満2型糖尿病モデルSDT fattyラットにおける非アルコール性脂肪肝炎発症の早期化の検討と各種薬剤の薬効評価
• Degree grantor/type: 新潟大学
• Date Granted: 2019-03-25
• Date Granted (W3CDTF): 2019-03-25
• Dissertation Number: 甲第4618号
• Degree Type: 博士（農学）
• Conferring No. (Dissertation): 甲第4618号
• Text Language Code: jpn
• Note (General): 3章までの結果から、肥満2型糖尿病を背景疾患として有するSDT fattyラットは、高コレステロール食給餌によって通常食給餌条件と比較して早期に脂肪肝を伴った肝線維化を発症し、病態解析によりその病態はヒトNASHに類似している部分がある可能性が示唆された。そこで、本章では糖尿病治療薬として代表的な薬剤であるピオグリタゾンとメトホルミンを用いてその効果について検証した。ピオグリタゾン投与により、高コレステロール食給餌雌性SDT fattyラットは血中インスリン値の低下を伴った血糖値の正常化を示し、また、血中脂質や血中AST、ALTの低下も確認できた。ただし、ピオグリタゾン投与群では顕著な体重の増加を伴っていた。また、ピオグリタゾン投与によって、肝脂質蓄積の改善効果や肝線維化関連遺伝子の低下効果、さらに肝病理組織学的評価では、脂肪肝、肝炎、肝線維化すべてにおける明らかな改善効果が確認できた。一方で、メトホルミン投与群では血糖値の低下効果は持続的に確認できたが、その他の血液生化学パラメータや脂肪肝、肝炎、肝線維化への改善効果は部分的であり、明らかな改善効果を示すまでには至らなかった。 今回の結果は、2型糖尿病を背景疾患に有するヒトNASH患者での有効性が報告されている薬剤であるピオグリタゾンと、ヒトNASH患者での臨床試験結果から有効性が明確ではないメトホルミンという関係性が高コレステロール食給餌雌性SDT fattyラットでも同様に表現されており、特に糖尿病を背景疾患とするヒトNASH患者をターゲットとした薬剤開発のための実験ツールとして、本モデルは高い価値を有する可能性が示唆された。; Nonalcoholic fatty liver disease (NAFLD) is associated with obesity, dyslipidemia, hypertension, type 2 diabetes and insulin resistance. NAFLD refers to the pathology of fatty livers ranging from simple steatosis through nonalcoholic steatohepatitis (NASH) to cirrhosis. Some of NAFLD cases lead to hepatocellular carcinoma. The pathogenesis of NASH seems to be poorly defined, and effective pharmacological therapies have not been approved all over the world. To understand the difficult features of NAFLD/NASH, animal models offer important information. Spontaneously Diabetic Torii (SDT) fatty rats, a new obese diabetic model, reportedly presented with features of NASH. Histopathological observations revealed NASH features at 32-40 weeks of age in female SDT fatty rat liver(Ishii et al., 2015).Female SDT fatty rats may be useful for NASH research. However, a long period of time is required prior to the onset of NASH. So, we tried to accelerate the onset of NASH in female SDT fatty rats using dietary fat or cholesterol loading. Result from our experiment, the onset of NASH in female SDT fatty rats appear to be accelerated by dietary cholesterol loading. Hepatic fibrosis was observed in female SDT fatty rats fed cholesterol-enriched diets (SDT fatty-Cho) from 16 weeks. In addition to pathophysiological analysis for female SDT fatty rat liver lesions, hepatic lipids, lipid peroxide and hepatic mRNA expression were evaluated. In the liver of female SDT fatty-Cho, hepatic triglyceride(TG), total cholesterol(TC), free fatty acid (FFA)and free cholesterol (FC) were higher than other groups. Hepatic mRNA expression related to Very Low density lipoprotein(VLDL) output decreased in SDT fatty-Cho, and the mRNA expression related to inflammation and fibrosis increased in SDT fatty-Cho. Furthermore, we investigated plasma choline concentrations in female SDT fatty rats. In human NASH patients, plasma choline concentrations are elevated, and it showed negative correlation with liver Microsomal triglyceride transfer protein(MTP) expression (Imajo et al., 2012). These results may be the phenotype of liver VLDL output impairment, which occurred in choline deficient diet NASH models (Kawaratani et al., 2008; Tsujimoto et al., 2008; Tsujimoto et al., 2009). SDT fatty-Cho showed increased plasma choline concentrations with decreased liver MTP expression, similar to human NASH. In addition to pathophysiological analysis, investigating the pharmacological effects of anti-diabetic drug on NASH to elucidate the properties of SDT fatty-Cho as a NASH animal model is very important. Currently, two anti-diabetic drugs, metformin and pioglitazone are clinically used as NASH therapies. However, both are not officially approved for NASH therapies, and this use is off-label. Pioglitazone reportedly showed the improvement effect of hepatic lesions in NASH therapy (Belfort et al., 2006; Sanyal et al., 2010; He et al., 2016), there is a recommendation in usage for NASH therapy. Metformin reportedly showed controversial result for the improvement effect for hepatic lesions (Nair et al., 2004). Metformin and pioglitazone repeatedly administered to female SDT fatty-Cho, and the effects of both drugs were investigated. From 4 weeks of age to 25 weeks of age, SDT fatty-Cho treated by pioglitazone 10 mg/kg or metformin 300 mg/kg. Pioglitazone treatment significantly reduced blood glucose, insulin, TG, TC, Aspartate aminotransferase and Alanine aminotransferase levels. Furthermore, pioglitazone treatment significantly decreased liver TG, TC, FFA and FC accumulation. The histological findings of livers in SDT fatty rats that received pioglitazone showed dramatically improvement of liver histology including inflammation and fibrosis. In addition to histological improvement, the mRNA expression in the liver related to VLDL output, inflammation and fibrosis improved by pioglitazone treatment. However, pioglitazone treatment caused significant increase of body weight according to increased food intake. Metformin treatment significantly reduced blood glucose levels. However, there are no improvement effects in any other blood parameters. The histological findings of the livers in metformin treatment group are limited. Only two animals showed histological improvement effects in this treatment group. In SDT fatty-Cho, pioglitazone improved hepatic lesions. However, the effects of metformin on hepatic lesions were partial. The SDT fatty-Cho showed different pharmacological responses to two anti-diabetic drugs, metformin and pioglitazone. These results in both drugs are quite similar to what is observed in human clinical trials. SDT fatty-Cho has the potential to become a valuable animal model for anti-NASH drugs that show potential to regulate glucose and lipid metabolism.; 学位の種類: 博士（農学）. 報告番号: 甲第4618号. 学位記番号: 新大院博（農）甲第190号. 学位授与年月日: 平成31年3月25日; 新大院博（農）甲第190号; 開始ページ : 1; 終了ページ : 83
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• Date Accepted (W3CDTF): 2019-08-03T12:23:27+09:00
• Date Created (W3CDTF): 2019-09-10
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• Periodical Title (URI): http://hdl.handle.net/10191/51335
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