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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 心筋症 / 7-ケトコレステロール / 脂肪肝炎 / 糖尿病

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.

Free Research Field

循環器内科学

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.