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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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Research Article Metabolism Article has an altmetric score of 1

LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice

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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 4

Selective regulation of GR target genes in Lxrα/β–/– mice treated with DEX.

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Selective regulation of GR target genes in Lxrα/β–/– mice treated with D...
WT and Lxrα/β–/– mice (6 months, male) were treated with 2.5 mg/kg DEX or vehicle (sesame oil) b.i.d. for 5 days. (A) Organic extracts of liver (~100–200 mg) were analyzed by LC/MS/MS for intra-hepatic DEX levels after chronic treatment with DEX (average ± SEM, n = 5). (B) Expression of GR from liver nuclear extracts of mice treated with DEX. Protein (40 μg/lane) was normalized for loading using the nuclear marker lamin B. Values represent the average GR protein level normalized to lamin B. (C and D) Real-time QPCR was performed on liver RNA. Gene expression changes were calculated using the comparative Ct method with cyclophilin as the reference gene and WT, vehicle as the calibrator. Samples exhibit non-LXR–selective and LXR-selective changes in gene expression (average ± SEM). n = 4–6 (C); n = 8–11 (D). *P < 0.05 by ANOVA and Student-Newman-Keuls.

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