Study identifies integrin αV–YAP–CTGF pathway linking liver congestion to fibrosis
A study from the University of Osaka identified the integrin αV–YAP–CTGF pathway linking chronic liver congestion to fibrosis. The findings point to a potential therapeutic target in congestion-related liver disease.
A recent study from the University of Osaka has discovered a molecular pathway connecting chronic liver congestion to liver fibrosis, portal hypertension and liver tumour development. The findings could help to inform new potential therapies and offer a potential new target for therapies to prevent serious liver disease.
Chronic liver congestion, also known as congestive hepatopathy, often progresses to liver fibrosis, cirrhosis and even liver cancer. While these associations have been well documented in medical literature, the specific molecular mechanisms linking congestion to fibrosis have remained largely unknown.
To investigate, the researchers focused on liver sinusoidal endothelial cells, or LSECs, which form the inner lining of the tiny blood vessels inside the liver and are directly affected when blood flow is blocked or slowed, such as during liver congestion. The team used single-cell and spatial transcriptomics to study liver samples from a mouse model of congestion and from patients with conditions such as Fontan-associated liver disease.
The analyses revealed increased activity of two molecules involved in cell signalling within LSECs: Yes-associated protein (YAP) and connective tissue growth factor (CTGF). The team also observed activation of the integrin pathway in the mouse model of liver congestion.
Using LSECs grown in the laboratory, the researchers showed that increased hydrostatic pressure, similar to that occurring during chronic liver congestion, activates YAP through integrin αV, which in turn upregulates CTGF. Inhibiting integrin αV or knocking out CTGF in LSECs improved outcomes in the mouse model, suggesting a potential therapeutic route.
The research team then examined liver samples from patients with chronic liver congestion. Single-cell and spatial transcriptomic analyses revealed the same pattern observed in mice: YAP activation in LSECs leading to increased CTGF levels. These changes are believed to contribute directly to disease progression.
Overall, the study identified the integrin αV–YAP–CTGF pathway in specialised liver blood vessel cells as a pathway that appears to connect liver congestion to fibrosis. Chronic liver congestion can lead to serious conditions such as liver fibrosis, portal hypertension and liver cancer, and it is particularly relevant for people with congenital heart disease who have undergone the Fontan procedure, as they are at risk of congestion-related liver damage.
The elevated pressure in the liver’s tiny blood vessels that occurs during chronic congestion also occurs in liver cirrhosis. The findings could inform the development of new treatments not only for patients with congestion-related liver disease but also for those with liver cirrhosis caused by other conditions.