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

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.