LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice
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
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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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 1

Lxrα/β–/– mice are hypercorticosteronemic but do not exhibit symptoms of Cushing syndrome.

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Lxrα/β–/– mice are hypercorticosteronemic but do not exhibit symptoms o...
(A) Circulating corticosterone from WT and Lxrα/β–/– mice (n = 4) measured at the peak of the circadian rhythm (10 pm, 2 hours after lights off). Plasma was analyzed for corticosterone level by LC/MS/MS. (B) Size comparison of 15-month-old male WT and Lxrα/β–/– mice. The size differential between the genotypes is most pronounced after 1 year of age. (C) Body weights of WT (n = 17) and Lxrα/β–/– (n = 36) mice at 6 months of age. Body fat (D) and plasma glucose (E) levels from WT and LXR-null mice measured by NMR minispec and tail nick, respectively (average ± SEM, n = 10). Mice used in C–E were male mice (6 month) fed a chow diet. *P < 0.05 versus WT (Student’s t test).