| First Author | Deans JR | Year | 2023 |
| Journal | Front Endocrinol (Lausanne) | Volume | 14 |
| Pages | 1266527 | PubMed ID | 38111711 |
| Mgi Jnum | J:343623 | Mgi Id | MGI:7568198 |
| Doi | 10.3389/fendo.2023.1266527 | Citation | Deans JR, et al. (2023) HNF4alpha isoforms regulate the circadian balance between carbohydrate and lipid metabolism in the liver. Front Endocrinol (Lausanne) 14:1266527 |
| abstractText | Hepatocyte Nuclear Factor 4alpha (HNF4alpha), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. P1-HNF4alpha is the major isoform in the adult liver while P2-HNF4alpha is thought to be expressed only in fetal liver and liver cancer. Here, we show that P2-HNF4alpha is indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4alpha we show that this isoform orchestrates a distinct transcriptome and metabolome via unique chromatin and protein-protein interactions, including with different clock proteins at different times of the day leading to subtle differences in circadian gene regulation. Furthermore, deletion of the Clock gene alters the circadian oscillation of P2- (but not P1-)HNF4alpha RNA, revealing a complex feedback loop between the HNF4alpha isoforms and the hepatic clock. Finally, we demonstrate that while P1-HNF4alpha drives gluconeogenesis, P2-HNF4alpha drives ketogenesis and is required for elevated levels of ketone bodies in female mice. Taken together, we propose that the highly conserved two-promoter structure of the Hnf4a gene is an evolutionarily conserved mechanism to maintain the balance between gluconeogenesis and ketogenesis in the liver in a circadian fashion. |
