| 研究実績の概要 |
Vitamin K (VK) acts as a ligand of pregnane X receptor (PXR) which is a predominant regulator of CYP7A1- the key enzyme of bile acids (BA) synthesis.VK deficiency is commonly observed in cholestasis.VK is capable of reducing the severity of cholestatic liver disease and the risk of mortality.However,the mechanism of the effect of VK on cholestasis-related liver disease is not revealed yet.The purpose of the current study is to reveal the mechanism of VK on BA synthesis and transportation via human PXR.
Till now,I have found that cholic acid (CA) administration for 1 or 2 weeks causes damage to the liver of hPXR female mice.Though ALP level was increased insignificantly,ALT,LAP,AST,total bilirubin,and BA level were increased significantly in the serum due to CA treatment.I have found that administration of menaquinone-4 (MK-4), a type 2 VK, tends to reduce the serum level of ALT,AST,LAP,and total BA in these mice.Unfortunately,I have found no significant effect of MK-4 treatment on the expression of genes related to BA in these CA treated mice.
Presently,I focus on finding the effect of VK deficiency on rat by analyzing BA metabolism-related proteins and transporters.Intestinal microbiome analysis will be done to analyze the relationship with the secondary BA content.I will analyze the effects of MK-4 on mRNA and proteins related to BA synthesis and transport in human liver-derived cells (HepaRG) and colon-derived cells (Caco-2).CRISPR cas9 technology will be used to create PXR-deficient cells and clarifies the mechanism of BA regulation through MK-4 mediated PXR activation.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
3: やや遅れている
理由
I followed the protocol that was already published in peer-reviewed journal to create cholestatic liver disease in the mice, but unfortunately only a few number of mice showed severe symptoms of the disease whereas other mice did not show much.
Moreover, getting enough number of homo knocked-in mice by breeding is time consuming.
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