HNF4α Isoforms Regulate the Circadian Balance Between Carbohydrate and Lipid Metabolism in the Liver

Authors

Jonathan R Deans
Poonamjot Deol
Nina Titova
Sarah H Radi
Linh M Vuong
Jane R Evans
Songqin Pan
Johannes Fahrmann
Jun Yang
Bruce D Hammock
Oliver Fiehn
Baharan Fekry
Kristin Eckel-Mahan
Frances M Sladek

Publication Date

12-4-2023

Journal

Frontiers in Endocrinology

Abstract

Hepatocyte Nuclear Factor 4α (HNF4α), a master regulator of hepatocyte differentiation, is regulated by two promoters (P1 and P2) which drive the expression of different isoforms. 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 indeed expressed in the normal adult liver at Zeitgeber time (ZT)9 and ZT21. Using exon swap mice that express only P2-HNF4α 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-)HNF4α RNA, revealing a complex feedback loop between the HNF4α isoforms and the hepatic clock. Finally, we demonstrate that while P1-HNF4α drives gluconeogenesis, P2-HNF4α 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.

Keywords

Animals, Female, Mice, Carbohydrates, Hepatocyte Nuclear Factor 4, Lipid Metabolism, Liver, Protein Isoforms, cytochrome P450, metabolic switch, sex-specific gene expression, fasting, circadian clock, ketogenesis, alternative promoter, nuclear receptor

Comments

Supplementary Materials

PMID: 38111711