Prevention study of obesity-associated liver disease by bariatric surgery

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K18096
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Oita University
• Principal Investigator: SAGA Kunihiro 大分大学, 医学部, 客員研究員 (50770145)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 肥満関連肝障害 / 肝星細胞 / 2次胆汁酸 / 肝細胞癌 / 腸内細菌叢

Outline of Final Research Achievements

We conducted a comprehensive DNA microarray study of the human HSC line LX-2 treated with Bile Acids (BAs). Additionally, LX-2 cells were exposed to nine BAs and studied using immunofluorescence staining, ELISA, and flow cytometry to examine the mechanisms of HSC activation. We focused on TNF pathway and revealed upregulation of genes related to NF-κB signaling and senescence-associated secretory phenotype factors. α-SMA was highly expressed in cells treated with secondary unconjugated BAs, and a morphological change associated with radial extension of subendothelial protrusion was observed. Interleukin-6 level in culture supernatant was significantly higher in cells treated with secondary unconjugated BAs. Flow cytometry showed that the proportion of cells highly expressing α-SMA was significantly increased in HSCs cultured with secondary unconjugated BAs. We demonstrated that secondary unconjugated BAs induced the activation of human HSCs.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

2次非抱合型胆汁酸がHSCの活性化に及ぼすメカニズムには細胞膜への直接作用やTNF signaling pathwayの上流に位置するレセプターに対する作用が考えられる。治療ターゲットとしてTLR阻害薬が種々の病態において注目されているが、未だ臨床上実用化されていない。
HSCの活性化は2次非抱合型胆汁酸により、最も強く誘導されることが示唆される。2次非抱合型胆汁酸によるHSCの強い活性化誘導は、肥満に起因する肝発癌のメカニズム解明、新たな治療ターゲットの開発につながると考えられた。