Elucidation of the mechanism of steatohepatitis-related cardiomyopathy due to dietary 7-ketocholesterol

2021 Fiscal Year Research-status Report

• Project/Area Number: 21K20870
• Research Institution: Osaka University
• Principal Investigator: 常 久洋 大阪大学, 医学系研究科, 招へい研究員 (60907707)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: 7-ketocholesterol / steatohepatitis / cardiac dysfunction / diabetes / cardomyopathy

Outline of Annual Research Achievements

An oxidized cholesterol, 7-ketocholesterol (7KC), is contained in processed food and plasma 7KC levels were significantly higher in patients with diabetes or cardiovascular diseases. In the previous study, I have examined that small amount of dietary 7KC induced hepatic steatosis and inflammation in obese mice (Chang J. et al. Front Endocrinol 2021).
In the current study, I examine whether small amount of dietary 7KC may exacerbate steatohepatitis and enhance cardiac dysfunction in mice. I hypothesize that dietary 7KC would activate inflammasome in liver and heart, leading to cardiac dysfunction. Alternatively, dietary 7KC would induce fatty liver and produce abnormal lipoprotein, resulting in lipid accumulation in mitochondria and reduce ATP production in cardiomyocytes.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

I examine my hypothesize in STZ-induced diabetic mice. After induction of type 2 diabetes in male mice, I fed high fat diet or NASH diet and analyzing hepatic and cardiac phenotypes. Currently, I observed cardiac inflammation in the 7KC-containing NASH diet group.

Strategy for Future Research Activity

Since I observed cardiac inflammation, I will examine cardiac function of those by using 7T-MRI or high performance ultrasonic cardiography.

Research Products

• [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 Pages: 2996
  • DOI: 10.1038/s41598-022-06542-8
• [Journal Article] Anti-GPIHBP1 Antibody-Positive Autoimmune Hyperchylomicronemia and Immune Thrombocytopenia (2022)
  • 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: - Pages: -
  • DOI: 10.5551/jat.63348
• [Presentation] Xcr1+ Dendritic Cell-Induced Cd4+ T Helper-1 Activation Leads to Exacerbation of Remodeling After Myocardial Infarction (2021)
  • Author(s): Inui H, Nishida M, Asaji M, Saga A, Kanno K, Jiuyang C, Zhu Y, Okada T, Tanaka K, Ohama T, Koseki M, Yamashita S, Sakata Y
  • Organizer: AHA2021 (American Heart Association)
  • Int'l Joint Research
• [Presentation] Targeted Next-generation Sequencing of 36 Lipid-Related Genes in Patients with Clinically Diagnosed Familial Hypercholesterolemia (2021)
  • Author(s): Okada T, Koseki M, Nishida M, Omatsu T, Tanaka K, Inui H, Chang J, Kanno K, Saga A, Ohama T, Ishihara M, Kujiraoka T, Hattori H, Masuda D, Yamashita S, Sakata Y
  • Organizer: AHA2021 (American Heart Association)
• [Presentation] Steatohepatitis-related Atherosclerosis and/or Cardiomyopathy in a Rodent Model (2021)
  • Author(s): Koseki M, Kanno K, Chang J, Saga A, Okada T, Inui H, Tanaka K, Omatsu T, Higo T, Ide S, Saito S, Kamada Y, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: ISA2021（国際動脈硬化学会） The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] 7-ketocholesterol exacerbates psoriasis-like dermatitis in diet-induced steatosis mice (2021)
  • Author(s): Saga A, Koseki M, Kanno K, Chang J, Tanaka K, Omatsu T, Nishihara S, Asaji M, Okada T, Kamada Y, Zhu Y, Inui H, Ohama T, Nishida M, Yamashita S, Sakata Y
  • Organizer: ISA2021（国際動脈硬化学会） The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] A case of anti-GPIHBP1 antibody positive hyperchylomicronemia accompanied with idiopathic thrombocytopenic purpura (2021)
  • Author(s): Tanaka K, Koseki M, Kato H, Chang J, Okada T, Kanno K, Inui H, Zhu Y, Ohama T, Nishida M, Miyashita K, Yamashita S, Sakata Y
  • Organizer: ISA2021（国際動脈硬化学会） 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): Okada T, Koseki M, Kato H, Tomita K, Matsui T, Tanaka K, Chang J, Inui H, Kanno K, Saga A, Ohama T, Ishihara M, Kujiraoka T, Hattori H, Nishida M, Yamashita S, Sakata Y
  • Organizer: ISA2021（国際動脈硬化学会） The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] Targeted Exon Sequencing of 36 Lipid-Related Genes in Patients with Clinically Diagnosed Familial Hypercholesterolemia (2021)
  • Author(s): Okada T, Koseki M, Nishida M, Omatsu T, Tanaka K, Inui H, Chang J, Kanno K, Saga A, Ohama T, Ishihara M, Kujiraoka T, Hattori H, Masuda D, Yamashita S, Sakata Y
  • Organizer: ISA2021（国際動脈硬化学会） The 19th International Symposium on Atherosclerosis
  • Int'l Joint Research
• [Presentation] 動脈硬化惹起食によって発症する脂肪肝炎関連心筋症のメカニズムの解明 (2021)
  • Author(s): 冠野昂太郎, 小関正博, 嵯峨礼美, 常久洋, 尾松卓, 田中克尚, 乾洋勉, 西原紗恵, 朝治真澄, 岡田健志, 大濱透, 西田誠, 鎌田佳宏, 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
  • Int'l Joint Research
• [Presentation] 7-ketocholesterolは食餌誘導性脂肪肝炎モデルマウスにおいて乾癬様皮膚炎を促進させる (2021)
  • Author(s): 嵯峨礼美, 小関正博, 冠野昂太郎, 常久洋, 田中克尚, 尾松卓, 朝治真澄, 岡田健志, 鎌田佳宏, 乾洋勉, 朱穎こう, 大濱透, 西田誠, 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
  • Int'l Joint Research
• [Presentation] 全身性に著明な腱黄色腫を認めた脳腱黄色腫症の一例 (2021)
  • Author(s): 尾松卓, 小関正博, 岡田健志, 田中克尚, 冠野昴太郎, 嵯峨礼美, 乾洋勉, 常久洋, 大濱透, 石原光昭, 鯨岡健, 服部浩明, 西田誠, 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
  • Int'l Joint Research
• [Presentation] 特発性血小板減少性紫斑病を伴う抗GPIHBP1抗体陽性自己免疫性高カイロミクロン血症の1例 (2021)
  • Author(s): 田中克尚, 小関正博, 加藤恒, 岡田健志, 嵯峨礼美, 冠野昴太郎, 常久洋, 乾洋勉, 朱頴こう, 大濱透, 西田誠, 宮下かずや, 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
  • Int'l Joint Research
• [Presentation] 心筋梗塞後に活性化したXCR1+樹状細胞によるTh1の誘導がリモデリングの増悪につながる (2021)
  • Author(s): 乾洋勉, 西田誠, 朝治真澄, 嵯峨礼美, 冠野昂太郎, 常久洋, 朱頴広, 岡田健志, 田中克尚, 大濱透, 小関正博, 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
  • Int'l Joint Research