SUN-023 HNF4a Isoforms Regulate the Circadian Balance between Carbohydrate and Fatty Acid Metabolism in the Liver

Nuclear receptor genes often contain alternative promoters but the physiological relevance of the different promoters or the proteins they generate is largely unknown. Hepatocyte Nuclear Factor 4α (HNF4α), master regulator of hepatocyte differentiation and the most abundant nuclear receptor in the liver, is regulated by two promoters (P1 and P2). P1-HNF4α, a tumor suppressor, is the major isoform in the adult liver while P2-HNF4α is expressed in fetal liver and liver cancer: a role for P2-HNF4α in normal adult liver has not been identified. Here we show for the first time that P2-HNF4α is expressed at ZT9 and ZT21 in the normal adult liver and use P2-HNF4α-expressing exon swap mice and ‘omics approaches to demonstrate that P2-HNF4α orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions. Cytochrome P450 and sex-specific gene expression is impacted as well as carbohydrate and fatty acid metabolism. The exon swap mice exhibit subtle differences in circadian gene regulation and disruption of the clock increases expression of P2-HNF4α. They also exhibit notable differences in carbohydrate versus fatty acid metabolism with P1-HNF4α driving gluconeogenesis and P2-HNF4α driving ketogenesis. Our results also show that P2-HNF4α is required for the elevated levels of ketone bodies in female mice. Taken together, we propose that the highly conserved two-promoter structure in the Hnfa gene is designed, at least in part, to respond to the availability of food resources and maintain the balance between gluconeogenesis and ketogenesis in a circadian and sex-specific fashion. (Funding: NIH NIDDK, West Cost Metabolomics Center, NIEHS T32, USDA NIFA, CCFA, Superfund Research Program)