EndocrinologyAug 21, 2026

BHLHE40 and ChREBP link to liver gene control regions with PPARα, RXRα, and HNF4 nuclear receptors

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Updated Aug 22, 2026

Abstract

BHLHE40/DEC1 binds to regulatory regions of the genome, showing extensive overlap with other transcription factors.

BHLHE40's genomic binding overlaps significantly with carbohydrate response-element binding protein (ChREBP), which regulates sugar sensing.
Knockdown of Bhlhe40 in mouse hepatocytes led to reduced expression of genes related to genomic stability.
Depletion of Bhlhe40 increased the liver's responsiveness to fructose, affecting cell cycle regulation genes.
BHLHE40's genomic binding aligns with enhancers associated with PPARα, RXRα, and HNF4 nuclear receptors.
BHLHE40 interacts physically with cofactors of RXRα and PPARα, suggesting a role in regulating hepatic gene expression.

Simplified

BHLHE40/DEC1 is a basic helix-loop-helix transcription factor (TF) that regulates circadian rhythm and T cell responses. In hepatocytes, its function and interplay with other TFs are poorly understood. Employing a genome-wide approach, we show that its genomic binding strongly overlapped with that of carbohydrate response-element binding protein (ChREBP), a sugar sensing TF and known inducer of BHLHE40 expression. Transcriptomic analysis of primary mouse hepatocytes revealed reduced expression of genes involved in genomic stability upon Bhlhe40 knock down by siRNA. Bhlhe40 depletion potentiated fructose responsiveness of genes involved in cell cycle regulation. Strikingly, genomic binding of BHLHE40 extensively overlapped with enhancers occupied by PPARα, RXRα, and HNF4 nuclear receptors and BHLHE40 fine-tuned the expression of PPARα target genes. Using HEK293 cells, we further observed that BHLHE40 physically interacted with RXRα and PPARα cofactors. Collectively, our data suggest that through cooperation with ChREBP and nuclear receptors, BHLHE40 is a central regulator of hepatic gene expression with potential to integrate inputs from nutrient signals contributing to the metabolic flexibility of the liver.

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BHLHE40 and ChREBP link to liver gene control regions with PPARα, RXRα, and HNF4 nuclear receptors

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