Elucidation of the Mechanism of Diabetic Cardiomyopathy Progression Due to Oxidized Sterol Accumulation

• Project/Area Number: 20K17149
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Osaka University
• Principal Investigator: Okada Takeshi 大阪大学, 医学系研究科, 寄附講座助教 (20750136)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 糖尿病性心筋症 / 脂肪肝炎 / 酸化ステロール / ミトコンドリア機能障害 / 心不全 / 非アルコール性脂肪肝炎 / 慢性炎症

Outline of Research at the Start

糖尿病性心筋症は糖尿病性心不全の前段階と考えられ、心筋肥大と拡張機能不全を特徴とするが、詳細な発症メカニズムは明らかでない。糖尿病患者では腸管の脂質吸収が亢進しており、最近になり血中の食事由来の酸化ステロール濃度が増加していると報告された。長期間に及ぶ微量の酸化ステロールの吸収・蓄積が、糖尿病性心筋症の進展に及ぼす影響とそのメカニズムについて、動物モデルを用いて明らかにする。

Outline of Final Research Achievements

We started this project with the hypothesis that long-term absorption of a small amount of dietary oxidized sterols (7-ketocholesterol (7KC)) may affect the development of diabetic cardiomyopathy. We have prepared diets with and without 7KC and fed them to diabetic ob/ob and db/db mice. The mice fed diet with 7KC showed no significant difference in heart weight or cardiac function, compared to those fed with normal diet. On the other hand, we found that addition of 7KC in chow diet or western type diet showed elevated serum ALT levels and accelerated hepatic neutral lipid accumulation and macrophages infiltration. RNA sequence analysis demonstrated that 7KC reduced expression of genes which related to autophagy process as well as beta-oxidation. We demonstrated that a small amount of dietary 7KC contributed to accelerate hepatic steatosis and inflammation in obese diabetic mice models.

Academic Significance and Societal Importance of the Research Achievements

本邦において糖尿病患者数は増加の一途を辿っている。糖尿病では腸管の脂質吸収が亢進しており、食事由来成分である酸化ステロールが糖尿病性心筋症を進展させる可能性を着想し、糖尿病マウスモデルを用いて検討した。本モデルでは心機能に有意な差を認めなかった一方で、少量の酸化ステロール長期摂取により、肝機能障害が惹起されることを見出し、そのメカニズムを解明した。脂肪肝炎もまた糖尿病の重要な予後規定因子であり、食事由来酸化ステロールが増悪因子となり得ることが示されたことで、新たな治療法の開発や栄養指導に対する重要なエビデンスにつながる研究であると言える。

Research Products

• [Journal Article] Anti-GPIHBP1 Antibody-Positive Autoimmune Hyperchylomicronemia and Immune Thrombocytopenia (2023)
  • Author(s): Tanaka Katsunao、Koseki Masahiro、Kato Hisashi、Miyashita Kazuya、Okada Takeshi、Kanno Kotaro、Saga Ayami、Chang Jiuyang、Omatsu Takashi、Inui Hiroyasu、Ohama Tohru、Nishida Makoto、Yamashita Shizuya、Sakata Yasushi
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 30 Issue: 1 Pages: 100-104
  • DOI: 10.5551/jat.63348
  • NAID: 130008161257
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2023-01-01
  • Peer Reviewed / Open Access
• [Journal Article] A Resuscitated Case of Acute Myocardial Infarction with both Familial Hypercholesterolemia Phenotype Caused by Possibly Oligogenic Variants of the <i>PCSK9</i> and <i>ABCG5</i> Genes and Type I CD36 Deficiency (2022)
  • Author(s): Nishikawa Ryo、Furuhashi Masato、Hori Mika、Ogura Masatsune、Harada-Shiba Mariko、Okada Takeshi、Koseki Masahiro、Kujiraoka Takeshi、Hattori Hiroaki、Ito Ryosuke、Muranaka Atsuko、Kokubu Nobuaki、Miura Tetsuji
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 29 Issue: 4 Pages: 551-557
  • DOI: 10.5551/jat.58909
  • NAID: 130007992205
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2022-04-01
  • Peer Reviewed / Open Access
• [Journal Article] Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy (2022)
  • Author(s): Kanno Kotaro、Koseki Masahiro、Chang Jiuyang、Saga Ayami、Inui Hiroyasu、Okada Takeshi、Tanaka Katsunao、Asaji Masumi、Zhu Yinghong、Ide Seiko、Saito Shigeyoshi、Higo Tomoaki、Okuzaki Daisuke、Ohama Tohru、Nishida Makoto、Kamada Yoshihiro、Ono Masafumi、Saibara Toshiji、Yamashita Shizuya、Sakata Yasushi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 2996-2996
  • DOI: 10.1038/s41598-022-06542-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distinct Differences in Lipoprotein Particle Number Evaluation between GP-HPLC and NMR: Analysis in Dyslipidemic Patients Administered a Selective PPARα Modulator, Pemafibrate (2021)
  • Author(s): Yamashita Shizuya、Okazaki Mitsuyo、Okada Takeshi、Masuda Daisaku、Yokote Koutaro、Arai Hidenori、Araki Eiichi、Ishibashi Shun
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 9 Pages: 974-996
  • DOI: 10.5551/jat.60764
  • NAID: 130008082098
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-09-01
  • Peer Reviewed / Open Access
• [Journal Article] Development and Clinical Application of an Enzyme-Linked Immunosorbent Assay for Oxidized High-Density Lipoprotein (2021)
  • Author(s): Okada Takeshi、Sumida Mizuki、Ohama Tohru、Katayama Yuki、Saga Ayami、Inui Hiroyasu、Kanno Kotaro、Masuda Daisaku、Koseki Masahiro、Nishida Makoto、Sakata Yasushi、Yamashita Shizuya
  • Journal Title: Journal of Atherosclerosis and Thrombosis Volume: 28 Issue: 7 Pages: 703-715
  • DOI: 10.5551/jat.56887
  • NAID: 130008060163
  • ISSN: 1340-3478, 1880-3873
  • Year and Date: 2021-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Dietary oxysterol, 7-Ketocholesterol accelerates hepatic lipid accumulation and macrophage infiltration in obese Mice (2021)
  • Author(s): J. Chang, M. oseki, A. Saga, K. Kanno, T. Higo, D. Okuzaki, T. Okada, H. Inui, K. Tanaka, M. Asaji, Y. Zhu, K. Yamada, M. Ono, T. Saibara, I Ichi, T. Ohama, M. Nishida, S. Yamashita, Y. Sakata
  • Journal Title: Front Endocrinol (Lausanne) Volume: 11 Pages: 614692-614692
  • DOI: 10.3389/fendo.2020.614692
  • Peer Reviewed / Open Access
• [Presentation] 40年以上通院加療中の家族性コレステロール血症ホモ接合体の一例 (2021)
  • Author(s): 岡田健志、小関正博、西田誠、尾松卓、田中克尚、乾洋勉、冠野昂太郎、嵯峨礼美、大濱透、山下静也、坂田泰史
  • Organizer: 第53回日本動脈硬化学会総会・学術集会
  • Invited
• [Presentation] 巨大血小板性血小板減少症と両側肘部黄色腫を契機に診断されたシトステロール血症の1例 (2021)
  • Author(s): 岡田健志、小関正博、加藤恒、冨田興一、松井崇浩、田中克尚、乾洋勉、冠野昂太郎、大濱透、西田誠、石原光昭、鯨岡健、服部浩明、山下静也、坂田泰史
  • Organizer: 第53回日本動脈硬化学会総会・学術集会
• [Presentation] 40年以上通院加療中の家族性コレステロール血症ホモ接合体の一例 (2021)
  • Author(s): 岡田健志、小関正博、西田誠、尾松卓、田中克尚、乾洋勉、冠野昂太郎、嵯峨礼美、大濱透、山下静也、坂田泰史
  • Organizer: 第55回日本成人病（生活習慣病）学会学術集会
• [Presentation] 巨大血小板性血小板減少症と両側肘部黄色腫を機に診断されたシトステロール血症の1例 (2021)
  • Author(s): 岡田健志、小関正博、尾松卓、田中克尚、乾洋勉、冠野昂太郎、嵯峨礼美、大濱透、西田誠、石原光昭、鯨岡健、服部浩明、山下静也、坂田泰史
  • Organizer: 第55回日本成人病（生活習慣病）学会学術集会
• [Presentation] 次世代シーケンサを用いた家族性高コレステロール血症患者の脂質関連36遺伝子変異解析 (2021)
  • Author(s): 岡田健志、小関正博、西田誠、尾松卓、田中克尚、乾洋勉、冠野昂太郎、嵯峨礼美、大濱透、石原光昭、鯨岡健、服部浩明、増田大作、山下静也、坂田泰史
  • Organizer: 第55回日本成人病（生活習慣病）学会学術集会
• [Presentation] A Case with Sitosterolemia Accompanied with Macrothrombocytopenia and Bilateral Elbow Tuberous Xanthomas (2021)
  • Author(s): Takeshi Okada, Masahiro Koseki, Hisashi Kato, Koichi Tomita, Katsunao Tanaka, Jiuyang Chang, Hiroyasu Inui, Kotaro Kanno, Ayami Saga, Tohru Ohama, Takeshi Kujiraoka, Hiroaki Hattori, Makoto Nishida, Shizuya Yamashita, Yasushi Sakata
  • Organizer: 89th European Atherosclerosis Society CONGRESS 2021
  • Int'l Joint Research
• [Presentation] Targeted Exon Sequencing of 36 Lipid-Related Genes in Patients with Clinically Diagnosed Familial Hypercholesterolemia (2021)
  • Author(s): Takeshi Okada, Masahiro Koseki, Makoto Nishida, Takashi Omatsu, Katsunao Tanaka, Hiroyasu Inui, Jiuyang Chang, Kotaro Kanno, Ayami Saga, Tohru Ohama, Mitsuaki Ishihara, Takeshi Kujiraoka, Hiroaki Hattori, Daisaku Masuda, Shizuya Yamashita, Yasushi Sakata
  • Organizer: The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] A Case with Sitosterolemia Accompanied with Macrothrombocytopenia and Bilateral Elbow Tuberous Xanthomas (2021)
  • Author(s): Takeshi Okada, Masahiro Koseki, Hisashi Kato, Koichi Tomita, Takahiro Matsui, Katsunao Tanaka, Jiuyang Chang, Hiroyasu Inui, Kotaro Kanno, Ayami Saga, Tohru Ohama, Mitsuaki Ishihara, Takeshi Kujiraoka, Hiroaki Hattori, Makoto Nishida, Shizuya Yamashita, Yasushi Sakata
  • Organizer: The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] Targeted Next-generation Sequencing of 36 Lipid-Related Genes in Patients with Clinically Diagnosed Familial Hypercholesterolemia (2021)
  • Author(s): Takeshi Okada, Masahiro Koseki, Makoto Nishida, Takashi Omatsu, Katsunao Tanaka, Hiroyasu Inui, Jiuyang Chang, Kotaro Kanno, Ayami Saga, Tohru Ohama, Mitsuaki Ishihara, Takeshi Kujiraoka, Hiroaki Hattori, Daisaku Masuda, Shizuya Yamashita, Yasushi Sakata
  • Organizer: American Heart Association 2021 Scientific Sessions
  • Int'l Joint Research
• [Presentation] 食餌由来7-ketocholesterolが糖尿病モデルラットの左室の収縮能、拡張能に及ぼす影響の検討 (2020)
  • Author(s): 岡田健志、小関正博、井手盛子、齋藤茂芳、常久洋、冠野昂太郎、乾洋勉、朱穎竑、大濱透、西田誠、山下静也、坂田泰史
  • Organizer: 第62回 日本脂質生化学会
• [Presentation] Targeted Exon Sequencing of Lipid-Related Genes in Patients with Familial Hypercholesterolemia (2020)
  • Author(s): Takeshi Okada, Masahiro Koseki, Makoto Nishida, Hiroyasu Inui, Kotaro Kanno, Ayami Saga, Tohru Ohama, Takeshi Kujiraoka, Hiroaki Hattori, Shizuya Yamashita, Yasushi Sakata
  • Organizer: 第52回日本動脈硬化学会総会・学術集会
• [Presentation] The Current Status of Achievement of Low-density Lipoprotein Cholesterol Management Targets in Familial Hypercholesterolemia Patients in Osaka University Hospital (2020)
  • Author(s): Takeshi Okada, Masahiro Koseki, Hiroyasu Inui, Kotaro Kanno, Jiuyang Chang, Yinghong Zhu, Ayami Saga, Masumi Asaji, Tohru Ohama, Makoto Nishida, Shizuya Yamashita, Yasushi Sakata
  • Organizer: 第84回日本循環器学会学術集会
• [Presentation] ヒト脂肪組織由来間葉系幹細胞を用いた劇症型心筋炎に対する新規治療法の開発 (2020)
  • Author(s): 岡田健志、小関正博、乾洋勉、田中克尚、常久洋、冠野昂太郎、嵯峨礼美、朱穎竑、朝治眞澄、倉田隼人、西田浩之、大濱透、西田誠、坂田泰史
  • Organizer: 第20回日本再生医療学会総会
• [Presentation] Targeted Exon Sequencing Reveals Overlapping of Lipid-Related Gene Variants in Patients with Clinically Diagnosed Familial Hypercholesterolemia (2020)
  • Author(s): Takeshi Okada, Masahiro Koseki, Makoto Nishida, Katsunao Tanaka, Hiroyasu Inui, Kotaro Kanno, Ayami Saga, Tohru Ohama, Takeshi Kujiraoka, Hiroaki Hattori, Shizuya Yamashita, Yasushi Sakata
  • Organizer: 第85回日本循環器学会学術集会
• [Presentation] Prevalence of Coronary Artery Disease and Achievement of Low-density Lipoprotein Cholesterol Management Targets in Familial Hypercholesterolemia Patients at Osaka University Hospital (2020)
  • Author(s): Takeshi Okada, Masahiro Koseki, Hiroyasu Inui, Kotaro Kanno, Ayami Saga, Tohru Ohama, Makoto Nishida, Shizuya Yamashita, Yasushi Sakata
  • Organizer: 88th European Atherosclerosis Society (EAS) Congress 2020
  • Int'l Joint Research
• [Presentation] Targeted Exon Sequencing of Lipid-Related Genes in Patients with Clinically Diagnosed Familial Hypercholesterolemia (2020)
  • Author(s): Takeshi Okada, Masahiro Koseki, Makoto Nishida, Katsunao Tanaka, Hiroyasu Inui, Kotaro Kanno, Ayami Saga, Tohru Ohama, Takeshi Kujiraoka, Hiroaki Hattori, Shizuya Yamashita, Yasushi Sakata
  • Organizer: American Heart Association (AHA) 2020 Scientific Sessions
  • Int'l Joint Research