LXRα Regulates ChREBPα Transactivity in a Target Gene-Specific Manner through an Agonist-Modulated LBD-LID Interaction.

Autor: Fan Q; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Nørgaard RC; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Grytten I; Department of Informatics, Faculty of Mathematics and Natural Sciences, University of Oslo, N-0317 Oslo, Norway., Ness CM; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Lucas C; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Vekterud K; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Soedling H; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Matthews J; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Lemma RB; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, N-0317 Oslo, Norway., Gabrielsen OS; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, N-0317 Oslo, Norway., Bindesbøll C; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Ulven SM; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Nebb HI; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Grønning-Wang LM; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway., Sæther T; Department of Molecular Medicine, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, N-0317 Oslo, Norway.
Jazyk: angličtina
Zdroj: Cells [Cells] 2020 May 13; Vol. 9 (5). Date of Electronic Publication: 2020 May 13.
DOI: 10.3390/cells9051214
Abstrakt: The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show that LXRα and ChREBPα interact physically and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP but not for LXR, indicating that ChREBPα recruits LXRα to chromatin in trans . The two factors interact via their key activation domains; the low glucose inhibitory domain (LID) of ChREBPα and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.
Databáze: MEDLINE
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