Inflammatory bowel disease (IBD) is a multifactorial disease with increasing incidence in the U.S. suggesting that environmental factors, including diet, are involved. It has been suggested that excessive consumption of linoleic acid (LA, C18:2 omega-6), which must be obtained from the diet, may promote the development of IBD in humans. To demonstrate a causal link between LA and IBD, we show that a high fat diet (HFD) based on soybean oil (SO), which is comprised of ~55% LA, increases susceptibility to colitis in several models, including IBD-susceptible IL10 knockout mice. This effect was not observed with low-LA HFDs derived from genetically modified soybean oil or olive oil. The conventional SO HFD causes classical IBD symptoms including immune dysfunction, increased intestinal epithelial barrier permeability, and disruption of the balance of isoforms from the IBD susceptibility gene Hepatocyte Nuclear Factor 4α (HNF4α). The SO HFD causes gut dysbiosis, including increased abundance of an endogenous adherent invasive Escherichia coli (AIEC), which can use LA as a carbon source. Metabolomic analysis shows that in the mouse gut, even in the absence of bacteria, the presence of soybean oil increases levels of LA, oxylipins and prostaglandins. Many compounds in the endocannabinoid system, which are protective against IBD, are decreased by SO both in vivo and in vitro . These results indicate that a high LA diet increases susceptibility to colitis via microbial and host-initiated pathways involving alterations in the balance of bioactive metabolites of omega-6 and omega-3 polyunsaturated fatty acids, as well as HNF4α isoforms.

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4α is the major isoform in the adult liver while P2-HNF4α is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4α is expressed at ZT9 and ZT21 in the normal adult liver and orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions. We demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α drives ketogenesis and is required for elevated levels of ketone bodies in females. Exon swap mice expressing only P2- HNF4α exhibit subtle differences in circadian gene regulation and disruption of the clock increases expression of P2-HNF4α. Taken together, we propose that the highly conserved two-promoter structure of the Hnfa gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion.

In the more than 30 years since the purification and cloning of Hepatocyte Nuclear Factor 4 (HNF4α), considerable insight into its role in liver function has been gleaned from its target genes and mouse experiments. HNF4α plays a key role in lipid and glucose metabolism and intersects with not just diabetes and circadian rhythms but also with liver cancer, although much remains to be elucidated about those interactions. Similarly, while we are beginning to elucidate the role of the isoforms expressed from its two promoters, we know little about the alternatively spliced variants in other portions of the protein and their impact on the 1000-plus HNF4α target genes. This review will address how HNF4α came to be called the master regulator of liver-specific gene expression with a focus on its role in basic metabolism, the contributions of the various isoforms and the intriguing intersection with the circadian clock.

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Hepatocyte Nuclear Factor 4α (HNF4α), the master regulator of liver-specific gene expression, is regulated by two promoters (P1 and P2) which drive expression of two groups of HNF4α isoforms referred to here as HNF4α1 and HNF4α7. HNF4α is a known regulator of gluconeogenesis and is mutated in maturity onset diabetes of the young one (MODY1). Conventionally, it was thought that HNF4α1, but not HNF4α7, is expressed in the normal adult liver, with HNF4α1 downregulated and HNF4α7 upregulated in liver cancer. Now, we identify a previously undescribed role for HNF4α7 in the normal adult mouse liver - one involved in the diurnal variations of lipid and carbohydrate metabolism. More specifically, HNF4α1 appears to be a major driver of gluconeogenesis while HNF4α7 is a driver of ketogenesis: we hypothesize that alterations in the levels of the HNF4α isoforms during the day function as a molecular switch between the two. Moreover, our preliminary data show that HNF4α7 is required for increased levels of circulating ketone bodies in female mice, suggesting interactions with the estrogen pathway. AMP-Activated Protein Kinase (AMPK), an energy-sensing kinase that also plays a major role in carbohydrate and lipid metabolism, has been shown to phosphorylate HNF4α1 in vitro, but effects in vivo and on HNF4α7 are not known. In order to investigate the impact of AMPK on HNF4α isoforms, we employed HNF4α isoform-specific mice α7HMZ (express only HNF4α7) and α1HMZ mice (express only HNF4α1), as well as heterozygous mice which express both. Intraperitoneal injection of the mice with AMPK activator AICAR leads to a rapid decrease in glucose. Interestingly, half the α7HMZ males and all the females began seizing 30 min post injection, while very few α1HMZ males/females and none of the heterozygous mice seized. Moreover, there were differences in the survival of the different genotypes: a third of α1HMZ mice die within 24hrs, while two thirds of α7HMZ mice die within a week, with all heterozygous mice surviving. We suspect the seizures could be due to an electrolyte imbalance exacerbated by AICAR or extremely low glucose caused by AICAR. The α7HMZ females have significantly lower potassium levels compared to α1HMZ and wildtype mice. Additionally, AMPK is known to regulate Na+/glucose transporters, and HNF4α1 is expressed in the proximal tubules in the kidney (responsible for Na+ uptake). To elucidate the cause of the seizures, AICAR injections were repeated with α1HMZ males followed by a glucose or saline gavage. Interestingly, half of the glucose-gavaged mice died within 24hrs, while all of the saline-gavaged mice survived. Our work underscores the critical role that the HNF4α isoforms play in the metabolic switch, and suggests that the kidney as well as the liver could be involved.