Influence of ketone body on the progression of nonalcoholic fatty liver disease

2018 Fiscal Year Final Research Report

• Project/Area Number: 15K19328
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Gastroenterology
• Research Institution: Kobe University
• Principal Investigator: Kawano Yuki 神戸大学, 医学研究科, 医学研究員 (80448175)
• Research Collaborator: TAGAWA Ryoma
• Project Period (FY): 2015-04-01 – 2019-03-31
• Keywords: 小胞体ストレス / ケトン体

Outline of Final Research Achievements

β-hydroxybutyrate (BHB), a ketone body in mammals, is produced from fatty acids in hepatocytes. To elucidate the role of BHB in the hepatic endoplasmic reticulum (ER), we examined the effects of BHB on ER stress. In Hepa1c1c7 cells, BHB suppressed the protein expression of ER stress responsive genes without causing alterations in the protein expression of sirtuin 1 (SIRT1). The intraperitoneal administration of BHB reduced the protein expression of ER stress responsive genes in mouse livers. In HepG2 cells, the protein expression levels of ER stress responsive genes were increased by the partial inhibition of BHB production with siRNA targeting endogenous 3-hydroxy-3-methylglutaryl coenzyme A lyase, whereas they were decreased by promoting BHB production with fenofibrate. These findings revealed that BHB helps to suppress hepatic ER stress via a SIRT1-independent pathway, and it might be possible to manipulate ER stress by regulating BHB production genetically or pharmacologically.

Free Research Field

肝臓病学

Academic Significance and Societal Importance of the Research Achievements

肝細胞内のβヒドロキシ酪酸（BHB）産生を操作することにより小胞体ストレスを制御できることを、我々は本研究により初めて報告した。小胞体ストレスは糖脂質代謝異常や非アルコール性脂肪性肝疾患の誘因となることから、BHB産生をコントロールすることでこれらの疾患を制御できる可能性を示した。