While ethanol metabolism in the liver occurs largely in hepatocytes, its oxidative product, acetaldehyde, easily diffuses to neighbours cells altering their physiologic processes. In the progression of ALD the activation of Hepatic Stellate Cells (HSCs) is a key step that leads to fibrosis and cirrhosis. Works by our group and others [50–52] demonstrated the importance of PPARγ in the activation of HSC. Active PPARγ is required for the maintenance of the resting “fat storing” phenotype by HSC, and its expression and transcriptional activity decrease during cell activation in culture. Moreover PDGF, a potent inducer of HSC proliferation and migration, induces inactivation of PPARγ by phosphorylation [50, 51]. The decrease in PPARγ transcriptional activity results in an increased synthesis of fibrillary collagens, while activation of the receptor by thiazolidinediones (TZDs) ligands was able to reduce the collagen synthesis in HSC both in vitro and in vivo [53]. The mechanism of PPARγ inhibition in human HSC by ethanol metabolism is rather complex. We found that acetaldehyde inhibits PPARγ by a MAPK mediated phosphorylation on Ser84. The phosphorylation of PPARγ was demonstrated to
