生物
脂肪变性
脂肪性肝炎
内分泌学
内科学
衰老
酪氨酸激酶
脂肪肝
癌症研究
细胞生物学
信号转导
医学
疾病
作者
Jialin Duan,Jingjing Liu,Bai Ruan,Jian Ding,Zhiqiang Fang,Hao Xu,Ping Song,Chi Xu,Zhiwen Li,Wei Du,Min Xu,Yu‐Wei Ling,Fangping He,Lin Wang
出处
期刊:Nature Aging
日期:2022-12-30
卷期号:3 (3): 258-274
被引量:11
标识
DOI:10.1038/s43587-022-00348-z
摘要
Aging leads to systemic metabolic disorders, including steatosis. Here we show that liver sinusoidal endothelial cell (LSEC) senescence accelerates liver sinusoid capillarization and promotes steatosis by reprogramming liver endothelial zonation and inactivating pericentral endothelium-derived C-kit, which is a type III receptor tyrosine kinase. Specifically, inhibition of endothelial C-kit triggers cellular senescence, perturbing LSEC homeostasis in male mice. During diet-induced nonalcoholic steatohepatitis (NASH) development, Kit deletion worsens hepatic steatosis and exacerbates NASH-associated fibrosis and inflammation. Mechanistically, C-kit transcriptionally inhibits chemokine (C–X–C motif) receptor (CXCR)4 via CCAAT enhancer-binding protein α (CEBPA). Blocking CXCR4 signaling abolishes LSEC–macrophage–neutrophil cross-talk and leads to the recovery of C-kit-deficient mice with NASH. Of therapeutic relevance, infusing C-kit-expressing LSECs into aged mice or mice with diet-induced NASH counteracts age-associated senescence and steatosis and improves the symptoms of diet-induced NASH by restoring metabolic homeostasis of the pericentral liver endothelium. Our work provides an alternative approach that could be useful for treating aging- and diet-induced NASH. The authors show that liver sinusoidal endothelial cell (LSEC) senescence promotes steatosis by reprogramming liver endothelial zonation and inhibiting C-kit, a type III receptor tyrosine kinase. Infusing C-kit-expressing LSECs in aged or diet-induced NASH mice counteracts senescence and steatosis.
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