Hepatocyte Nuclear Factor 4α Coordinates a Transcription Factor Network Regulating Hepatic Fatty Acid Metabolism

Adaptation of liver to nutritional signals is regulated by several transcription factors that are modulated by intracellular metabolites. Here, we demonstrate a transcription factor network under the control of hepatocyte nuclear factor 4 alpha (HNF4 alpha) that coordinates the reciprocal expression of fatty acid transport and metabolizing enzymes during fasting and feeding conditions. Hes6 is identified as a novel HNF4 alpha target, which in normally fed animals, together with HNF4 alpha, maintains PPAR gamma expression at low levels and represses several PPAR alpha-regulated genes. During fasting, Hes6 expression is diminished, and peroxisome proliferator-activated receptor alpha (PPAR alpha) replaces the HNF4 alpha/Hes6 complex on regulatory regions of target genes to activate transcription. Gene expression and promoter occupancy analyses confirmed that HNF4 alpha is a direct activator of the Ppar alpha gene in vivo and that its expression is subject to feedback regulation by PPAR alpha and Hes6 proteins. These results establish the fundamental role of dynamic regulatory interactions between HNF4 alpha, Hes6, PPAR alpha, and PPAR gamma in the coordinated expression of genes involved in fatty acid transport and metabolism.