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

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 3

Insulin tolerance is maintained in DEX-treated Lxrα/β–/– mice.

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Insulin tolerance is maintained in DEX-treated Lxrα/β–/– mice. (A an...
(A and B) WT and Lxrα/β–/– mice were treated with DEX or vehicle for 5 days. Plasma insulin (A) and free fatty acids (B) were measured in the fed state using commercially available kits. (C–E) Mice were treated with DEX or vehicle for 7 days and fasted for 4 hours prior to performing the OGTT (C, D) and ITT (E) tests. (C and D) Mice were gavaged with 20% D-glucose (2 g/kg) and blood sampled from a tail nick at different time points. Plasma glucose (C) was assayed using a colorimetric kit, and plasma insulin (D) from the glucose tolerance test was assayed by RIA. (E) Insulin was injected i.p. at 0.75 U/kg, and plasma was assayed at regular intervals to measure glucose. The definitions of circles and squares in part C also apply to parts D and E. Mice were injected with saline or insulin (1.5 U/kg, i.p.) 5 minutes prior to sacrifice. Liver extracts (20 μg) were immunoblotted using antibodies against p-Akt and normalized against total Akt (F). Samples were run on the same gel but were noncontiguous. Data shown are average ± SEM. n = 4 (A and B); n = 7 (C and D); n = 6–7 (E). *P < 0.05, ANOVA followed by Student-Newman-Keuls. In line graphs C–E, asterisks indicate significant difference from Lxrα/β–/– mice with the same treatment regimen. #P < 0.05, ANOVA followed by Student-Newman-Keuls, significantly different from vehicle-treated control of same genotype.