Researchers at the University of Osaka report that chronic liver congestion (congestive hepatopathy) drives severe liver disease through a pressure-sensitive signaling pathway in liver sinusoidal endothelial cells (LSECs), and have identified molecular targets that may help prevent fibrosis, portal hypertension, and liver cancer. The study, published in Gastroenterology, details how increased venous pressure in the liver activates the integrin αV–YAP–CTGF axis in LSECs and promotes fibrogenesis and tumorigenesis in congestive hepatopathy.
Hepatic congestion is a result of a significant and persistent increase in hepatic venous pressure caused by congenital heart disease, right-sided heart failure, Budd-Chiari syndrome, and other conditions. It leads to fibrosis around central veins in the liver and in the tiny blood vessels in the liver that surround its central vein. This will progress to bridging fibrosis from central veins to other central veins or to portal tracts, a pattern known as ‘inverse lobulation,’ without clear evidence of inflammation. In addition, liver disease following the Fontan procedure, known as Fontan-associated liver disease (FALD), is an increasing concern as more children with congenital heart disease survive into adulthood.
A prolonged period of these conditions and worsening symptoms can eventually lead to cirrhosis and liver tumors. Although these symptoms have long been recognized, the molecular biology that drives venous stasis to fibrogenesis have been unknown.
To address this knowledge gap, the Osaka team applied single-cell RNA sequencing to samples of livers from the mouse models of disease and discovered activation of the integrin signaling pathway and yes-associated protein (YAP) in pericentral LSECs, where fibrosis first develops in congestive hepatopathy. Connective tissue growth factor (CTGF) was the most strongly upregulated gene in these cells.
The researchers developed further evidence of the role played by YAP by increasing hydrostatic pressure in vitro, designed to mimic the elevated sinusoidal pressure in congestive hepatopathy. Doing so activated YAP, increased CTGF and type IV collagen (COL4) expression in LSECs, which then stimulated type I collagen (COL1) and COL4 expression in hepatic stellate cells, the main drivers of fibrosis.
“In the present study, we demonstrated in a mouse model and in a cell culture system that hepatic congestion led to YAP activation and YAP-dependent CTGF overproduction in LSECs, which play essential roles in liver fibrosis, portal hypertension, and liver tumorigenesis. Furthermore, single-cell analysis of human FALD samples revealed that YAP activation and increased CTGF expression in LSECs also occur in humans,” the researchers wrote.
These findings build on previous studies that showed LSECs respond to mechanical forces such as shear stress and stretch. However, as the researchers noted, “the role of YAP/TAZ in the mechano-stress response in LSECs and their response to hydrostatic pressure have never been examined.” By identifying a hydrostatic pressure–responsive integrin αV–YAP–CTGF axis, the study provides an explanation for how venous hypertension alone, even in the absence of inflammation, can drive fibrosis and cancer.
Clinically, the work has implications for patients with Fontan-associated liver disease and other forms of congestive hepatopathy, as well as for cirrhosis from other causes where sinusoidal pressure is elevated. Therapeutic strategies could include integrin αV inhibitors, some of which already have been developed and tested in liver diseases. Other approaches could include targeting YAP or CTGF in LSECs using cell-specific delivery systems such as lipid nanoparticles.
The authors note that the study is limited by the small number of clinical samples and that further accumulation and evaluation of FALD cases will be needed. Future work will likely focus on validating CTGF as a biomarker, refining LSEC-targeted therapies, and determining how modulation of this pathway affects long-term outcomes in patients with congestive hepatopathy.
