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At least five million people in Germany suffer from liver disease. Fibrosis, the pathological proliferation of connective tissue, plays an important role in many complications of chronic liver problems. Activated hepatic stellate cells (HSCs) are heavily involved in this tissue remodeling. An international research team led by Prof. Dr. Ingmar Mederacke, Managing Director, has now found an approach to reduce the activation of HSCs and the associated development of liver fibrosis. The work has been published in the renowned journal Science Translational Medicine.
Hepatic stellate cells produce connective tissue
Liver fibrosis and the final stage of liver fibrosis, liver cirrhosis, are a major medical problem for which no suitable drugs are yet available. The best-known causes include chronic alcohol consumption, infection with hepatitis viruses, but also medication or a fatty liver. The pathogenic stimuli damage the liver cells, the so-called hepatocytes. They die and trigger an inflammatory reaction. Until now, it was not known how this inflammatory process activates the hepatic stellate cells. The HSCs are located in the blood vessel walls in the immediate vicinity of the hepatocytes, where they primarily store vitamin A during the resting phase. However, when they are activated, they transform into myofibroblasts and produce an abnormally large amount of connective tissue.
"We looked at which substances are released when hepatocytes die and how exactly these molecules are linked to fibrosis formation," says Professor Mederacke. The research team discovered that certain stored, activated sugar molecules (UDP-glucose and UDP-galactose) are released during hepatocyte cell death. These can bind precisely to a protein called P2Y14 as so-called ligands. "We found the P2Y14 receptor primarily in the liver stellate cells," explains the physician.
P2Y14 receptor as a link between cell death and fibrosis formation
In the mouse model, the research team examined the signaling pathway between the P2Y14 ligand and receptor. Increased release of these activated sugar molecules led to activation of the stellate cells. In contrast, inactivation of the P2Y14 receptor reduced fibrosis formation. "We were also able to detect the P2Y14 receptor in human hepatic stellate cells using special antibodies," says the hepatologist. The connection between the cell death of the liver tissue and the formation of fibrosis has also been confirmed in studies of healthy and diseased human livers. The discovery could be an important step towards an anti-fibrotic therapy. The next step would be to find an antagonist that can block the P2Y14 receptor and thus reduce the development of liver fibrosis.
For further information, please contact Prof. Dr. Ingmar Mederacke, mederacke.ingmar@mh-hannover.de, telephone (0511) 532-6619.