Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a ligand-activated transcription factor belonging, together with PPAR gamma and PPAR beta/delta, to the NR1C nuclear receptor subfamily. Many PPARa target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPAR alpha activation, in combination with PPAR beta/delta agonism, improves steatosis, inflammation and fibrosis in pre-clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPAR alpha, the spectrum of target genes and chromatin-binding maps from recent genomewide studies, paying particular attention to PPAR alpha-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPAR alpha, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data. (C) 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.