The adaptive hypoxia system of the prolyl hydroxylases (PHD) in the pathophysiology of Non-Alcoholic Steatohepatitis (NASH)

Non-Alcoholic SteatoHepatitis (NASH) is characterized by liver inflammation with concurrent fat accumulation and is a frequent and rising cause of chronic liver diseases. Up till now, no efficient medical treatments are available. Previous experimental studies show that anti-angiogenetic approaches in NASH might be beneficial. More recently, a new paradigm has arised in which not the amount of blood vessels is important, but the vessel ‘quality’ is targeted. Prolyl hydroxylases (PHD) are the key oxygen sensors of our cells and PHD deficiency results in vessel normalization, restorage of endothelial cell dysfunction and less hypoxia in tumours. First, we would like to characterize the hepatic and intestinal expression of the different PHD isoforms in human NASH and in two validated NASH mouse models. We have already preliminary data showing differential PHD expression in human NASH livers, but this will be further characterized. Secondly, we will examine the effects of PHD inhibition by dimethyloxalylglycine (DMOG, a pan-PHD inhibitor) in experimental NASH. Thirdly, we will evaluate vessel-normalizing strategies in experimental NASH models by using selective endothelial PHD knock-out and PHD overexpression animals. Besides the hepatic effects of PHDs, the impact on the splanchnic vascular bed, and more in detail the splanchnic vasodilation and hyperdynamic circulation associated with cirrhosis, will be studied before and after endothelial normalization.