PMID:17107947

Citation	Cha, JY and Repa, JJ (2007) The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J. Biol. Chem. 282:743-51
Abstract	The liver X receptors, LXRalpha (NR1H3) and LXRbeta (NR1H2), are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. LXRs play a critical role in cholesterol homeostasis and bile acid metabolism. In addition, oral administration of LXR agonists to mice results in elevated hepatic fatty acid synthesis and steatosis and increased secretion of triglyceride-rich very low density lipoprotein resulting in hypertriglyceridemia. This increased hepatic lipogenesis has been largely attributed to the LXR-dependent up-regulation of sterol regulatory element-binding protein 1c (SREBP-1c) expression. However, it has been reported that treating Srebp-1c null mice with the synthetic LXR agonist T0901317 still results in enhanced expression of many lipogenic genes, suggesting additional mechanisms by which LXR can enhance hepatic lipogenesis. In this report, we identify the carbohydrate response element-binding protein (ChREBP) as an LXR target that independently enhances the up-regulation of select lipogenic genes. The ChREBP promoter contains functional LXR-binding sites that confer receptor-dependent binding and transactivation. We show that T0901317 treatment of mice is associated with up-regulation of the ChREBP target gene, liver-type pyruvate kinase. Therefore, activation of LXR not only increases ChREBP mRNA via enhanced transcription but also modulates ChREBP activity. This establishes LXR as a master lipogenic transcription factor, as it directly regulates both SREBP-1c and ChREBP to enhance hepatic fatty acid synthesis.
Links	PubMed Online version:10.1074/jbc.M605023200
Keywords	Animals; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/metabolism; Fatty Acids/metabolism; Humans; Hydrocarbons, Fluorinated; Liver/metabolism; Mice; Mice, Inbred C57BL; Nuclear Proteins/metabolism; Nuclear Proteins/physiology; Orphan Nuclear Receptors; Promoter Regions, Genetic; Protein Binding; Receptors, Cytoplasmic and Nuclear/chemistry; Receptors, Cytoplasmic and Nuclear/metabolism; Response Elements; Sterol Regulatory Element Binding Protein 1/genetics; Sterol Regulatory Element Binding Protein 1/metabolism; Sulfonamides/pharmacology; Transcription Factors/metabolism; Transcription Factors/physiology; Transcriptional Activation; Triglycerides/chemistry
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
MOUSE:RXRA	part_of	GO:0090575: RNA polymerase II transcription regulator complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:RXRA	contributes_to	GO:0004879: nuclear receptor activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:RXRA	contributes_to	GO:0000976: transcription regulatory region sequence-specific DNA binding	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:RXRA	involved_in	GO:0045944: positive regulation of transcription by RNA polymerase II	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:NR1H3	part_of	GO:0090575: RNA polymerase II transcription regulator complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:NR1H3	contributes_to	GO:0000976: transcription regulatory region sequence-specific DNA binding	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:NR1H3	contributes_to	GO:0004879: nuclear receptor activity	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete
MOUSE:NR1H3	part_of	GO:0090575: RNA polymerase II transcription factor complex	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
MOUSE:NR1H3	involved_in	GO:0045944: positive regulation of transcription by RNA polymerase II	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
MOUSE:NR1H3	contributes_to	GO:0044212: transcription regulatory region DNA binding	ECO:0000314: direct assay evidence used in manual assertion		F		Seeded From UniProt	complete

References

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