The Fox Genes in the Liver: From Organogenesis to Functional Integration

Abstract

Formation and function of the liver are highly controlled, essential processes. Multiple signaling pathways and transcriptional regulatory networks cooperate in this complex system. The evolutionarily conserved FOX, for Forkhead bOX, class of transcriptional regulators is critical to many aspects of liver development and function. The FOX proteins are small, mostly monomeric DNA binding factors containing the so-called winged helix DNA binding motif that distinguishes them from other classes of transcription factors. We discuss the biochemical and genetic roles of Foxa, Foxl1, Foxm1, and Foxo, as these have been shown to regulate many processes throughout the life of the organ, controlling both formation and function of the liver.

DNA methylation alters transcriptional rates of differentially expressed genes and contributes to pathophysiology in mice fed a high fat diet

“…Summaries of these genes, along with a brief description of their functions, are listed in Supplemental Table 5. Of note is that Onecut1 and Foxa3 are both important for liver development [17], [18], and the Phlda1 global knockout model presents with a phenotype of increased adult body mass and liver steatosis, even on a standard chow diet [19].…”

“…Importantly, all of the genes in the subnetwork were significantly decreased after a high fat diet as determined by RNAseq (see comparison, Supplemental Table 5). Included in this gene list were Foxa1 and Foxa2 , paralogs of Foxa3 , which are required for liver development and are important for the expression of numerous metabolic enzymes involved in glucose and lipid homeostasis [17]. Also included was Irx3 , which is involved in weight homeostasis in the hypothalamus, though its role in the liver is not fully understood [45].…”

“…A subset of co-regulated genes was identified by investigating nearest neighbors of Phlda1 in a Bayesian network previously generated from F2 crossed mouse liver transcriptomic data [14], [15], [16]. Onecut1 , and Foxa family members (Forkhead Box A 1–3) were among several genes in the subnetwork that were decreased by a high fat diet and are important for liver development, liver phenotype, and lipid homeostasis [17], [18]. Furthermore, knockdown of Phlda1 led to increased lipid droplet size.…”

FOXN3 Regulates Hepatic Glucose Utilization

“…Since the discovery of fkh and its mammalian orthologs, numerous paralogs have been identified in vertebrates, with Mendelian diseases including familial cancer syndromes, immune deficiencies, glaucoma and speech disorders being caused by mutations in human FOX genes (Hannenhalli and Kaestner, 2009). Several FOX family members have “neo-functionalized” in higher vertebrates to govern specific aspects of metabolism (Benayoun et al, 2011; Le Lay and Kaestner, 2010). For instance, FOXO is firmly established as a master regulator of hepatic glucose production.…”

Physical Activity Offsets the Negative Effects of a High-Fructose Diet

“…Fructose is almost exclusively phosphorylated to fructose-1-phosphate in an ATP-dependent process catalyzed by fructokinase in hepatic cells. This results in a rapid and relatively unregulated production of triose-phosphates which may subsequently be converted to pyruvate for conversion to lactate or acetyl CoA (34). Large concentrations of acetyl CoA can stimulate hepatic de novo lipogenesis (DNL) and simultaneously inhibit hepatic lipid oxidation resulting in fatty acid re-esterification and VLDL-triglyceride synthesis (31).…”