Research Themes

• Involvement of heme metabolic disorders in hepatocytes in the development of nonalcoholic steatohepatitis.
  Grant-in-Aid for Scientific Research (C)
  Teikyo Heisei University
  Apr. 2019 - Mar. 2022
  It has been suggested that abnormal iron metabolism is associated with the development and progression of non-alcoholic steatohepatitis (NASH), but the mechanism of this association remains unclear. In this study, we focused on the heme biosynthesis pathway, one of the iron utilization pathways in hepatocytes, as a factor linking the onset and progression of NASH and abnormal iron metabolism, and examined the relationship between heme biosynthesis pathway and NASH. The results suggest that the heme biosynthesis pathway in hepatocytes is impaired under methionine and choline deficiency conditions, which is one of the methods used to create animal models of NASH. We also found that an inducer of HO-1, a heme degrading enzyme, reduced the cytotoxicity of tamoxifen, one of the causative agents of NASH.
• C型肝炎時の肝細胞内ヘム代謝に着目した薬剤性肝障害メカニズムの解明
  Apr. 2016 - Mar. 2018
• Investigation of the link between hepatitis C and porphyria cutanea tarda
  Grant-in-Aid for Young Scientists (B)
  Teikyo Heisei University
  Apr. 2015 - Mar. 2018
  Earlier reports have shown a high prevalence of hepatitis C virus (HCV) infection in patients with PCT. While these observations implicate HCV infection as a risk factor for PCT pathogenesis, the mechanism of interaction between the virus and porphyrin metabolism is unknown. Here, we showed that HCV core protein triggers abnormal porphyrin metabolism, expressed by excess coproporphyrin excretion and higher porphyrins synthesis rate, via the change in the expression of enzymes and transporters involved in heme synthesis pathway. In addition, we confirmed that HCV core protein strengthen the ethanol-induced increase in ALAS1 protein expression that is a rate-limiting enzyme in heme synthesis.
• Analysis of idiosyncratic drug toxicity using mitochondria isolated from an animal model of metabolic syndrome
  Grant-in-Aid for Challenging Exploratory Research
  Teikyo Heisei University
  Apr. 2014 - Mar. 2016
  Although it has been suggested that underlying disease could be a nongenetic risk factor for idiosyncratic drug-induced liver injury (DILI), little is known about the mechanisms that determine the increased sensitivity to DILI. In addition to patient risk factors, drug related risk factors including mitochondrial toxicity have also been proposed to explain the complex mechanisms of DILI. The objective of this study was to determine whether the fatty liver in type 2 diabetes (T2D) is more susceptible to mitochondrial permeability transition (MPT), characterized by swelling and membrane depolarization that are associated with DILI. Our result showed that T2D enhanced susceptibility to drug-induced MPT. We also demonstrated that the liver mitochondria isolated from T2D mice had increased oxygen consumption stimulated by an uncoupler compared to normal liver mitochondria (NLM). It might be a useful tool to predict DILI in T2D patients, because its sensitivity to drug is different from NLM.