title: Identification of HNF-4α as a key transcription factor to promote ChREBP expression in response to glucose.
abstract: Transcription factor carbohydrate responsive element binding protein (ChREBP) promotes glycolysis and lipogenesis in metabolic tissues and cancer cells. ChREBP-α and ChREBP-β, two isoforms of ChREBP transcribed from different promoters, are both transcriptionally induced by glucose. However, the mechanism by which glucose increases ChREBP mRNA levels remains unclear. Here we report that hepatocyte nuclear factor 4 alpha (HNF-4α) is a key transcription factor for glucose-induced ChREBP-α and ChREBP-β expression. Ectopic HNF-4α expression increased ChREBP transcription while knockdown of HNF-4α greatly reduced ChREBP mRNA levels in liver cancer cells and mouse primary hepatocytes. HNF-4α not only directly bound to an E-box-containing region in intron 12 of the ChREBP gene, but also promoted ChREBP-β transcription by directly binding to two DR1 sites and one E-box-containing site of the ChREBP-β promoter. Moreover, HNF-4α interacted with ChREBP-α and synergistically promoted ChREBP-β transcription. Functionally, HNF-4α suppression reduced glucose-dependent ChREBP induction. Increased nuclear abundance of HNF-4α and its binding to cis-elements of ChREBP gene in response to glucose contributed to glucose-responsive ChREBP transcription. Taken together, our results not only revealed the novel mechanism by which HNF-4α promoted ChREBP transcription in response to glucose, but also demonstrated that ChREBP-α and HNF-4α synergistically increased ChREBP-β transcription.
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Meng
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Feng
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Dong
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Yemin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Yakui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Wu
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Minle
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Endocrinology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665, Kong Jiang Road, Shanghai, 200092, China.
authors.forename: Hanbei
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197, Rui-Jin 2nd Road, Shanghai, 200025, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Haipeng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai, 200025, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Tong
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D017930:Genes, Reporter; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics* / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059372:Nucleotide Motifs; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; C116385:MLXIPL protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D008156:Luciferases; D005947:Glucose