Evidence for an indirect transcriptional regulation of glucose-6-phosphatase gene expression by liver X receptors.
Liver X receptor (LXR) paralogues alpha and beta (LXRalpha and LXRbeta) are members of the nuclear hormone receptor family and have oxysterols as endogenous ligands. LXR activation reduces hepatic glucose production in vivo through the inhibition of transcription of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase). In the present study, we investigated the molecular mechanisms involved in the regulation of G6Pase gene expression by LXR. Both T0901317, a synthetic LXR agonist, and the adenoviral overexpression of either LXRalpha or LXRbeta suppressed G6Pase gene expression in H4IIE hepatoma cells. However, compared to the suppression of G6Pase expression seen by insulin, the decrease of G6Pase mRNA by LXR activation was delayed and was blocked by cycloheximide, an inhibitor of protein synthesis. These observations, together with the absence of a conserved LXR-binding element within the G6Pase promoter, suggest an indirect inhibition of G6Pase gene expression by liver X receptors.
Grempler
Rolf
R
Department of Medical Biochemistry and Molecular Biology, University of Greifswald, D-17487 Greifswald, Germany. rolfgrempler@yahoo.de
Günther
Susanne
S
Steffensen
Knut R
KR
Nilsson
Maria
M
Barthel
Andreas
A
Schmoll
Dieter
D
Walther
Reinhard
R
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D005952:Glucose-6-Phosphatase / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D005952:Glucose-6-Phosphatase