| 配分額 *注記 |
4,680千円 (直接経費: 3,600千円、間接経費: 1,080千円)
2025年度: 1,560千円 (直接経費: 1,200千円、間接経費: 360千円)
2024年度: 1,300千円 (直接経費: 1,000千円、間接経費: 300千円)
2023年度: 1,820千円 (直接経費: 1,400千円、間接経費: 420千円)
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| 研究実績の概要 |
Dual specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). In this study, we used a high-fat diet (HFD)-induced murine non-alcoholic fatty liver disease (NAFLD) model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficient (HI) mice developed severe obesity and liver pathology consistent with NAFLD when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, while hepatocytes from Dusp6-KO mice showed minimal lipid accumulation. Transcriptome analysis revealed significant downregulation of genes encoding cytochrome P450 4A (CYP4A), known to promote ω-hydroxylation of fatty acids and hepatic steatosis, in Dusp6-KO hepatocytes compared with WT hepatocytes. Diminished CYP4A expression was observed in the liver of Dusp6-KO mice compared to WT and Dusp6-HI mice. Knockdown of DUSP6 in HepG2, a human liver-linage cell line, also promoted a reduction of lipid accumulation, downregulation of CYP4A, and upregulation of phosphorylated/activated MAPK. Furthermore, inhibition of MAPK activity promoted lipid accumulation in DUSP6-knockdown HepG2 cells without affecting CYP4A expression, indicating that CYP4A expression is independent of MAPK activation. These findings highlight the significant role of DUSP6 in HFD-induced steatohepatitis through two distinct pathways involving CYP4A and MAPK.
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