Sladek, F. M. | bioRxiv Science

bioRxiv2021

HNF4α isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver

Hepatocyte Nuclear Factor 4 (HNF4), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2). P1-HNF4 is the major isoform in the adult liver while P2-HNF4 is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2- HNF4 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-HNF4 drives gluconeogenesis, P2-HNF4 drives ketogenesis and is required for elevated levels of ketone bodies in females. Exon swap mice expressing only P2- HNF4 exhibit subtle differences in circadian gene regulation and disruption of the clock increases expression of P2-HNF4. 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.

genomics↗

bioRxiv2021

Diet High in Soybean Oil Increases Susceptibility to Colitis in Mice

The current American diet is high in soybean oil (SO), which consists of unsaturated fatty acids, most notably linoleic acid (LA, C18:2 omega-6). While LA is an essential fatty acid that must be obtained from the diet, high LA consumption has been linked to the development of inflammatory bowel disease (IBD) in humans. Here, we show that a high fat diet (HFD) based on soybean oil increases susceptibility to colitis in wild-type and IL10 knockout mice. It causes immune dysfunction, decreases colon and crypt length and increases intestinal epithelial barrier permeability; these effects were not observed in low LA HFDs. The SO diet also disrupts the balance of isoforms encoded by the IBD susceptibility gene Hepatocyte Nuclear Factor 4 (HNF4). Both the SO diet and an LA gavage cause gut dysbiosis: the SO diet increases the abundance of an adherent, invasive Escherichia coli (AIEC), which can use LA as a carbon source, and the LA gavage decreases the beneficial bacteria Lactobacillus murinus. Metabolomic analysis of both host-associated and cultured bacteria shows that SO increases levels of LA and oxylipins while decreasing eicosapentaenoic acid (EPA, C20:5 omega-3) and endocannabinoids. Our results suggest that excess LA, obtained from a diet high in soybean oil, increases susceptibility to colitis by alterations in intestinal HNF4, gut microbiota and bioactive metabolites.

physiology↗