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␣ (HNF4␣) that coordinates the reciprocal expression of fatty acid transport and metabolizing enzymes during fasting and feeding conditions. Hes6 is identified as a novel HNF4␣ target, which in normally fed animals, together with HNF4␣, maintains PPAR␥ expression at low levels and represses several PPAR␣-regulated genes. During fasting, Hes6 expression is diminished, and peroxisome proliferator-activated receptor ␣ (PPAR␣) replaces the HNF4␣/Hes6 complex on regulatory regions of target genes to activate transcription. Gene expression and promoter occupancy analyses confirmed that HNF4␣ is a direct activator of the Ppar␣ gene in vivo and that its expression is subject to feedback regulation by PPAR␣ and Hes6 proteins. These results establish the fundamental role of dynamic regulatory interactions between HNF4␣, Hes6, PPAR␣, and PPAR␥ in the coordinated expression of genes involved in fatty acid transport and metabolism.Hepatic fatty acid metabolism is a tightly controlled process that involves regulation at the levels of uptake, oxidation, de novo synthesis, and export to the circulation. Regulation is achieved by the action of hormones, like insulin, or intracellular metabolites, notably fatty acids and sterols, that can activate transcription factors, including nuclear hormone receptors (peroxisome proliferator-activated receptor [PPAR␣ or NR1C1], PPAR␥ [NR1C3], liver X receptor ␣ [LXR␣ or NR1H3]), the carbohydrate response element binding protein ChREBP, and the sterol regulated factor SREBP1c (5,16,20,41). Activities of these transcription factors are subject to modulation by phosphorylation, by regulated shuttling between the cytoplasm and the nucleus, by exchange of coregulators on target promoters, and by intracellular metabolites that function as ligands. PPAR␣ and PPAR␥ are key regulators of genes encoding proteins involved in fatty acid uptake, storage, and degradation (31). Various intracellular fatty acids, particularly unsaturated fatty acids and eicosanoids, derived from arachidonic acid, prostaglandin J2, or linoleic acid can bind to the ligand-binding domains of PPAR␣ and PPAR␥ (5, 31). Fatty acid ligands promote heterodimerization of PPAR␣ with retinoid X receptor (RXR) and their binding to the PPAR response elements (PPRE) at target promoters to initiate transcription activation (15).Ligand-dependent activation of PPAR␣ and PPAR␥ provides the principal mechanisms for sensing changes in the concentrations of intracellular metabolites during hormonal or nutrient signaling. Earlier observations, however, suggested that expression of these transcription factors is also subject to regulation in the liver. For example, PPAR␥ is expressed at low levels in hepatocytes, reduced during fasting, and activated during high-fat diet feeding (14,30,39). PPAR␥ mRNA levels are h...

Hepatocyte nuclear factor 4␣ (HNF-4␣) is a transcription factor which is highly expressed in the intestinal epithelium from duodenum to colon and from crypt to villus. The homeostasis of this constantly renewing epithelium relies on an integrated control of proliferation, differentiation, and apoptosis, as well as on the functional architecture of the epithelial cells. In order to determine the consequences of HNF-4␣ loss in the adult intestinal epithelium, we used a tamoxifen-inducible Cre-loxP system to inactivate the Hnf-4a gene. In the intestines of adult mice, loss of HNF-4␣ led to an increased proliferation in crypts and to an increased expression of several genes controlled by the Wnt/␤-catenin system. This control of the Wnt/␤-catenin signaling pathway by HNF-4␣ was confirmed in vitro. Cell lineage was affected, as indicated by an increased number of goblet cells and an impairment of enterocyte and enteroendocrine cell maturation. In the absence of HNF-4␣, cell-cell junctions were destabilized and paracellular intestinal permeability increased. Our results showed that HNF-4␣ modulates Wnt/␤-catenin signaling and controls intestinal epithelium homeostasis, cell function, and cell architecture. This study indicates that HNF-4␣ regulates the intestinal balance between proliferation and differentiation, and we hypothesize that it might act as a tumor suppressor.