肝细胞
JAG1
纤维化
脂肪性肝炎
脂肪肝
生物
Notch信号通路
肝活检
非酒精性脂肪肝
癌症研究
细胞生物学
内科学
内分泌学
病理
医学
信号转导
活检
生物化学
体外
疾病
作者
Junjie Yu,Changyu Zhu,Xiaobo Wang,Kyeong Jin Kim,Alberto Bartolomé,Paola Dongiovanni,Katherine P. Yates,Luca Valenti,Michele Carrer,Thorsten Sadowski,Qiang Li,Ira Tabas,Joel E. Lavine,Utpal B. Pajvani
出处
期刊:Science Translational Medicine
[American Association for the Advancement of Science (AAAS)]
日期:2021-06-23
卷期号:13 (599)
被引量:42
标识
DOI:10.1126/scitranslmed.abe1692
摘要
Aberrant hepatocyte Notch activity is critical to the development of nonalcoholic steatohepatitis (NASH)-induced liver fibrosis, but mechanisms underlying Notch reactivation in developed liver are unclear. Here, we identified that increased expression of the Notch ligand Jagged1 (JAG1) tracked with Notch activation and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) in human liver biopsy specimens and mouse NASH models. The increase in Jag1 was mediated by hepatocyte Toll-like receptor 4 (TLR4)-nuclear factor κB (NF-κB) signaling in pericentral hepatocytes. Hepatocyte-specific Jag1 overexpression exacerbated fibrosis in mice fed a high-fat diet or a NASH-provoking diet rich in palmitate, cholesterol, and sucrose and reversed the protection afforded by hepatocyte-specific TLR4 deletion, whereas hepatocyte-specific Jag1 knockout mice were protected from NASH-induced liver fibrosis. To test therapeutic potential of this biology, we designed a Jag1-directed antisense oligonucleotide (ASO) and a hepatocyte-specific N-acetylgalactosamine (GalNAc)-modified siRNA, both of which reduced NASH diet-induced liver fibrosis in mice. Overall, these data demonstrate that increased hepatocyte Jagged1 is the proximal hit for Notch-induced liver fibrosis in mice and suggest translational potential of Jagged1 inhibitors in patients with NASH.
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