LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice
Rucha Patel, … , David J. Mangelsdorf, Carolyn L. Cummins
Rucha Patel, … , David J. Mangelsdorf, Carolyn L. Cummins
Published December 1, 2010
Citation Information: J Clin Invest. 2011;121(1):431-441. https://doi.org/10.1172/JCI41681.
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LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

Abstract

Although widely prescribed for their potent antiinflammatory actions, glucocorticoid drugs (e.g., dexamethasone) cause undesirable side effects that are features of the metabolic syndrome, including hyperglycemia, fatty liver, insulin resistance, and type II diabetes. Liver x receptors (LXRs) are nuclear receptors that respond to cholesterol metabolites and regulate the expression of a subset of glucocorticoid target genes. Here, we show LXRβ is required to mediate many of the negative side effects of glucocorticoids. Mice lacking LXRβ (but not LXRα) were resistant to dexamethasone-induced hyperglycemia, hyperinsulinemia, and hepatic steatosis, but remained sensitive to dexamethasone-dependent repression of the immune system. In vivo, LXRα/β knockout mice demonstrated reduced dexamethasone-induced expression of the key hepatic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK). In perfused liver and primary mouse hepatocytes, LXRβ was required for glucocorticoid-induced recruitment of the glucocorticoid receptor to the PEPCK promoter. These findings suggest a new avenue for the design of safer glucocorticoid drugs through a mechanism of selective glucocorticoid receptor transactivation.

Authors

Rucha Patel, Monika Patel, Ricky Tsai, Vicky Lin, Angie L. Bookout, Yuan Zhang, Lilia Magomedova, Tingting Li, Jessica F. Chan, Conrad Budd, David J. Mangelsdorf, Carolyn L. Cummins

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Figure 6

Recruitment of GR to the PEPCK promoter is decreased in livers of Lxrβ–/– and Lxrα/β–/– mice.

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Recruitment of GR to the PEPCK promoter is decreased in livers of Lxrβ–/...
(A) Primary hepatocytes were seeded on 6-well collagen-coated plates and treated with vehicle (DMSO) or DEX (10 nM) for 16 hours. RNA was extracted, reverse transcribed, and analyzed for gene expression by real-time QPCR. Data pooled from 2 independent experiments (average ± SEM, n = 5–6). (B and C) ChIP of GR protein from mice perfused with vehicle or 10 nM DEX through the portal vein for 30 minutes. The negative control region for PEPCK was at –3 kb relative to the transcription start site. Chromatin was pooled from 2 mice per treatment, and results are expressed relative to percentage of input and normalized to GR vehicle (Veh) for each genotype. Error bars represent PCR amplification variability (average ± SD, n = 3). The values for the GR Ab PEPCK and TAT GREs prior to normalization were as follows: WT (0.08, 0.05); Lxrα–/– (0.06, 0.08); Lxrβ–/– (0.06, 0.02); Lxrα/β–/– (0.08, 0.02). *P < 0.05 ANOVA and Student-Newman-Keuls. Fold changes are indicated on the graphs.