During the development of chronic liver disease, all sinusoidal cells play a key role. Endothelial cells are the first cells to become the differentiated to become activated and this contribute to the progression of the disease, but also other sinusoidal cells like hepatic stellate cells, which are the hepatic myofibroblasts and also the hepatic macrophages which are called cuffer cells. All these cells change their phenotype due to the chronic injury and contribute to the progression of the disease and its clinical complications. One of the most important complications of chronic liver disease in NASH is portal hypertension, which is due to an increment in the intrahepatic vascular resistance due to the disease. Its development is a campaign by clinical or high morbidity and mortality.
From a therapeutic point of view we know that PPARs, which are ligand activated transcription factors, can modulate the phenotype of all sinusoidal cells. We have some evidence that activation of PPAR alpha and PPAR gamma or PPAR delta may contribute to the improvement in sinusoidal cells, especially endothelial cells, stellate cells and macrophages. Just to give you an example, if we are able to improve the phenotype of the stellate cells by acting on PPAR delta or PPAR gamma, we are able to modulate their phenotype, reduce their activation and improve fibrosis. This is due to our reduction in the profibrogenic content that is released by hepatic stellate cells. On the other hand, the hepatic stellate cells contract and their contraction elevates the vascular tone and the development of portal pressure.