| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2016: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
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| Outline of Annual Research Achievements |
The aim is to elucidate the mechanisms and potential molecular targets of micronutrient antioxidants, such as carotenoids, on lipotoxicity-induced insulin resistance, inflammation, and fibrosis in non-alcoholic steatohepatitis (NASH). According to the research plan in 2016, we first found that CX3CR1 was predominantly expressed in F4/80+ macrophages compared with hepatic stellate cells or endothelial cells in the liver NASH mice. FACS analysis also revealed that, compared with chow-fed mice, NASH mice exhibited a significant increase in CX3CR1+ expression in liver macrophages (LMs), particularly M1 LMs. CX3CR1 deficiency caused a significant increase of inflammatory monocytes/macrophages infiltration and an M1 dominant shift of macrophages in the liver, thereby exacerbated the progression of NASH. Moreover, transplantation of Cx3cr1-/- BM was sufficient to impair glucose tolerance, inflammation and fibrosis in the liver. In addition, deletion of CCL2 in Cx3cr1-/- mice alleviated NASH progression by decreasing macrophage infiltration and an M2 dominant shift of LMs. Importantly, overexpression of CX3CL1 in vivo protected against hepatic fibrosis in NASH. These results suggested that CX3CR1-/- NASH mice can be considered an exacerbated NASH model. On the other hand, CCR5-/- mice showed opposite effect on the pathogenesis of NASH. CCR5 deficiency induced a significant decrease of macrophage infiltration and M2-dominant shift in the liver, as well as improved hepatic insulin resistance and inflammation. Thereby, CCR5-/- NASH mice can be considered an improved NASH model.
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