Student and Faculty Publications
HNF4α Isoforms Regulate the Circadian Balance Between Carbohydrate and Lipid Metabolism in the Liver
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
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Bioinformatics Commons, Biomedical Informatics Commons, Endocrinology, Diabetes, and Metabolism Commons, Genetics and Genomics Commons, Internal Medicine Commons, Medical Biochemistry Commons, Medical Cell Biology Commons
Comments
Supplementary Materials
PMID: 38111711