REZONABLE · Regeneration and zonation by ZEB2 of Liver Endothelium

Regeneration and zonation by ZEB2 of Liver Endothelium

The liver plays an essential role in metabolism. It is responsible for the uptake and detoxification of ingested toxins and drugs as well as the removal of waste products from the body. In addition, the liver plays a key role in glucose and lipid metabolism and produces various bioactive proteins including albumin and clotting factors. Liver disease is a common health problem and can be caused by various hepatotoxins including alcohol and drugs, by fat accumulation and by viral infection. The early stage of liver disease is liver fibrosis. It is a slow and reversible condition but remains asymptomatic until it progresses to cirrhosis. Cirrhosis reduces liver function and patients show various symptoms including jaundice, fatigue, bleedings and abdominal fluid accumulation and they have a high risk to develop liver cancer. There is no medication available to cure or reduce cirrhosis, the only cure for patients with liver cirrhosis is liver transplantation. To accommodate its functions, the liver has a unique vascular system. It receives a mix of nutrient-rich blood from the portal vein and oxygen-rich blood from the hepatic artery, which flows through the hepatic sinusoids and is eventually collected in the central vein. All blood vessels are lined on the inside with endothelial cells (ECs). The hepatic sinusoids are lined with an endothelium consisting of highly specialised liver sinusoidal ECs (LSECs). To facilitate transport of agents to and from the hepatocytes, LSECs have fenestrae, intracellular gaps and lack a basement membrane. In addition, they express LSEC marker genes including several scavenger receptors to take up macromolecules from the blood. LSECs are known to play a role in liver disease, since they lose their specific characteristics already before the onset of fibrosis. We therefore hypothesised that LSECs represent a promising target to develop medication to cure and diagnose liver disease in an early stage. The liver is zonated, i.e., the hepatocytes around the portal triad where the blood enters have a different function than those around the central vein. For example, the hepatocytes on the portal side are important in glucose production whereas the hepatocytes around the central vein are more important for triglyceride production and toxin removal. LSECs also show morphological signs of zonation but little is known about how zonation is regulated in LSECs and how LSEC marker genes are distributed across the hepatic sinusoids. Transcription factors (TFs) are proteins that regulate the expression of other proteins. Previously, the host lab identified 7 TFs that are highly expressed in LSECs and 23 LSEC-enriched marker genes. In this study, we aimed to evaluate the role TFs in LSEC marker expression and the zonation of these proteins. In addition, we evaluated how one of the identified TFs (‘TFA’) affects the liver vasculature in healthy and diseased livers.

Data: CORDIS, © European Union