Fig. 7.

Characteristics of liver sinusoidal endothelial cells during disease progression. Chronic liver damage can be experimentally induced by toxic substances such as carbon tetrachloride (CCl₄) and thioacetamide (TAA) administration, surgical interventions such as bile duct ligation, as well as dietary models of non-alcoholic steatohepatitis (NASH) including methionine- and choline-deficient diets (MCD) and the choline-deficient L-amino-defined diet (CDAA). LSEC maintain liver homeostasis through nitric oxide (NO) synthesis and secreting angiocrine factors such as Wnt2, Wnt9b, HGF, BMP2, p300 mediated CCL2, and heparin-binding EGF-like growth factor (HB-EGF). The transcription factor GATA4 controls the sinusoidal phenotype including the absence of a basement membrane. During liver homeostasis, autophagic activity of LSEC is increased to protect against liver injury, and there is only little deposition of ECM molecules in the space of Disse. GATA4 is downregulated and continuous EC genes including the transcription factor Myc and the angiocrine factor Pdgfb are upregulated in NASH-induced perisinusoidal fibrosis. The balance between CXCR7 and CXCR4 shifts and further favors the pro-fibrotic pathways upon toxic liver injury. During fibrosis, angiocrine factors including TGF-β, PDGFB, SDF1, and Hh are dynamically upregulated. Activated LSEC may further trigger HSC to produce excessive ECM. NO bioavailability is lost and the autophagic activity is reduced