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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, 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 on Bhlhe40 knockdown 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 PPAR\u03b1, RXR\u03b1, and HNF4 nuclear receptors and BHLHE40 fine-tuned the expression of PPAR\u03b1 target genes. Using HEK293 cells, we further observed that BHLHE40 physically interacted with RXR\u03b1 and PPAR\u03b1 cofactors. Collectively, our data suggest that through cooperation with carbohydrate response-element binding protein 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.<\/jats:p>","DOI":"10.1210\/endocr\/bqag095","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T11:47:12Z","timestamp":1787226432000},"source":"Crossref","is-referenced-by-count":1,"title":["BHLHE40 and ChREBP associate with hepatic enhancer clusters containing PPAR\u03b1, RXR\u03b1, and HNF4 nuclear receptors"],"prefix":"10.1210","volume":"167","author":[{"given":"Krista","family":"Kokki","sequence":"first","affiliation":[{"name":"Faculty of Biological and Environmental Sciences, University of Helsinki , 00790 Helsinki ,","place":["Finland"]},{"name":"Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki , 00790 Helsinki 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