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JCI Insight ; 9(11)2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38713515

RESUMO

Portal hypertension (PHTN) is a severe complication of liver cirrhosis and is associated with intrahepatic sinusoidal remodeling induced by sinusoidal resistance and angiogenesis. Collagen type IV (COL4), a major component of basement membrane, forms in liver sinusoids upon chronic liver injury. However, the role, cellular source, and expression regulation of COL4 in liver diseases are unknown. Here, we examined how COL4 is produced and how it regulates sinusoidal remodeling in fibrosis and PHTN. Human cirrhotic liver sample RNA sequencing showed increased COL4 expression, which was further verified via immunofluorescence staining. Single-cell RNA sequencing identified liver sinusoidal endothelial cells (LSECs) as the predominant source of COL4 upregulation in mouse fibrotic liver. In addition, COL4 was upregulated in a TNF-α/NF-κB-dependent manner through an epigenetic mechanism in LSECs in vitro. Indeed, by utilizing a CRISPRi-dCas9-KRAB epigenome-editing approach, epigenetic repression of the enhancer-promoter interaction showed silencing of COL4 gene expression. LSEC-specific COL4 gene mutation or repression in vivo abrogated sinusoidal resistance and angiogenesis, which thereby alleviated sinusoidal remodeling and PHTN. Our findings reveal that LSECs promote sinusoidal remodeling and PHTN during liver fibrosis through COL4 deposition.


Assuntos
Colágeno Tipo IV , Células Endoteliais , Hipertensão Portal , Cirrose Hepática , Fígado , Hipertensão Portal/metabolismo , Hipertensão Portal/patologia , Hipertensão Portal/genética , Animais , Colágeno Tipo IV/metabolismo , Colágeno Tipo IV/genética , Camundongos , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Cirrose Hepática/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/genética , Fígado/patologia , Fígado/metabolismo , Fígado/irrigação sanguínea , Masculino , NF-kappa B/metabolismo , Camundongos Endogâmicos C57BL , Epigênese Genética
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