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

• Project/Area Number: 21K20870
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Osaka University
• Principal Investigator: Chang Jiuyang 大阪大学, 大学院医学系研究科, 招へい研究員 (60907707)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 心筋症 / 7-ケトコレステロール / 脂肪肝炎 / 糖尿病 / 7-ketocholesterol / steatohepatitis / cardiac dysfunction / diabetes / cardomyopathy / oxysterol / NAFLD / cardiomyopathy / inflammation

Outline of Research at the Start

It has been demonstrated that CVD including atherosclerosis and heart failure is the leading cause of mortality among patients with Non-alcoholic fatty liver disease (NAFLD). However, the genetic background which induces both NAFLD and CVD is still unclear. We have focused on a dietary factor, oxysterol in processed foods, and demonstrated that oxysterol accelerated hepatic lipid accumulation and inflammation in obese mice. In this study, I hypothesize that dietary oxysterol might induce cardiomyopathy with steatohepatitis.

Outline of Final Research Achievements

C57Bl/6 mice were injected STZ (160mg/kg) intraperitoneally and confirmed that the blood glucose levels were in the range of 200-350 mg/dL two weeks after injection. Diabetic mice were fed high fat diet with or without 7KC for four or twelve weeks and sacrificed. In STZ-induced diabetic mice, oil Red O staining showed more and larger lipid droplets in WD+-KC. Lipid extraction analysis has demonstrated that triglycerides and free cholesterol were significantly increased in liver in WD+7KC group. Serum ALT and TNF-a were significantly increased in WD+7KC and F4/80 staining exhibited increased macrophages in WD+7KC. Pathway analysis by RNA sequencing demonstrated that several pathways, such as TNF signaling pathway were upregulated in WD+7KC. Importantly, in heart, inflammatory cytokine, IL-1b was upregulated in WD+7KC. In summary, dietary supplementation of 7KC accelerated cardiac inflammation through hepatic steatosis, inflammatory cell infiltration and fibrosis.

Academic Significance and Societal Importance of the Research Achievements

It has been demonstrated that cardiovascular disease is the leading cause of mortality among patients with non-alcoholic fatty liver diseases. We have demonstrated that 7KC in diet might accelerate cardiac inflammation through hepatic steatosis and inflammation by NLRP3 inflammasome activation.

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 Dietary Oxysterol, 7-Ketocholesterol, Exacerbates Imiquimod-Induced Psoriasis-like Dermatitis in Steatohepatitic Mice (2022)
  • Author(s): Saga Ayami、Koseki Masahiro、Kanno Kotaro、Chang Jiuyang、Higo Tomoaki、Yamashita Shizuya、Sakata Yasushi
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 24 Pages: 15855-15855
  • DOI: 10.3390/ijms232415855
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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
• [Presentation] The Hepatic Lipid Type And Content Had An Impact On Hepatic Inflammation And Fibrosis In Streptozotocin-induced Diabetic Mice (2022)
  • Author(s): Masahiro Koseki, Jiuyang Chang, Ayami Saga, Kotara Kanno, Katsunao Tanaka, Takashi Omatsu, Takeshi Okada, Hiroyasu lnui, Tohru Ohama, Makoto Nishida, Yasushi Sakata
  • Organizer: American Heart Association Scientific Session 2022
  • Int'l Joint Research
• [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