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

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

doi:10.3389/fendo.2023.1266527

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

Front Endocrinol (Lausanne). 2023 Dec 4:14:1266527. doi: 10.3389/fendo.2023.1266527. eCollection 2023.

Authors

Jonathan R Deans^{1

2}, Poonamjot Deol^#¹, Nina Titova^#¹, Sarah H Radi^#^{1

3}, Linh M Vuong^#¹, Jane R Evans¹, Songqin Pan⁴, Johannes Fahrmann⁵, Jun Yang⁶, Bruce D Hammock⁶, Oliver Fiehn⁵, Baharan Fekry⁷, Kristin Eckel-Mahan^{7

8}, Frances M Sladek¹

Affiliations

¹ Department of Molecular, Cell and Systems Biology, University of California, Riverside, Riverside, CA, United States.
² Genetics, Genomics and Bioinformatics Graduate Program, University of California, Riverside, Riverside, CA, United States.
³ Biochemistry and Molecular Biology Graduate Program, University of California, Riverside, Riverside, CA, United States.
⁴ Proteomics Core, Institute for Integrative Genome Biology, University of California, Riverside, Riverside, CA, United States.
⁵ National Institutes of Health West Coast Metabolomics Center, University of California, Davis, Davis, CA, United States.
⁶ Department of Entomology and Nematology & UCD Comprehensive Cancer Center, University of California, Davis, Davis, CA, United States.
⁷ Department of Biochemistry and Molecular Biology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, United States.
⁸ Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, TX, United States.

^# Contributed equally.

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: alternative promoter; circadian clock; cytochrome P450; fasting; ketogenesis; metabolic switch; nuclear receptor; sex-specific gene expression.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carbohydrates
Female
Hepatocyte Nuclear Factor 4* / genetics
Hepatocyte Nuclear Factor 4* / metabolism
Lipid Metabolism* / genetics
Liver / metabolism
Mice
Protein Isoforms / genetics
Protein Isoforms / metabolism

Substances

Carbohydrates
Hepatocyte Nuclear Factor 4
Protein Isoforms
Hnf4a protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding