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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)431-441
Number of pages11
JournalJournal of Clinical Investigation
Volume121
Issue number1
DOIs
StatePublished - Jan 4 2011

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Hyperglycemia
Glucocorticoids
Liver
Dexamethasone
Phosphoenolpyruvate
Glucocorticoid Receptors
Hyperinsulinism
Fatty Liver
Cytoplasmic and Nuclear Receptors
Knockout Mice
Pharmaceutical Preparations
Type 2 Diabetes Mellitus
Transcriptional Activation
Genes
Insulin Resistance
Hepatocytes
Immune System
Anti-Inflammatory Agents
Cholesterol

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Patel, R., Patel, M., Tsai, R., Lin, V., Bookout, A. L., Zhang, Y., ... Cummins, C. L. (2011). LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. Journal of Clinical Investigation, 121(1), 431-441. https://doi.org/10.1172/JCI41681

LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. / Patel, Rucha; Patel, Monika; Tsai, Ricky; Lin, Vicky; Bookout, Angie L.; Zhang, Yuan; Magomedova, Lilia; Li, Tingting; Chan, Jessica F.; Budd, Conrad; Mangelsdorf, David J.; Cummins, Carolyn L.

In: Journal of Clinical Investigation, Vol. 121, No. 1, 04.01.2011, p. 431-441.

Research output: Contribution to journalArticle

Patel, R, Patel, M, Tsai, R, Lin, V, Bookout, AL, Zhang, Y, Magomedova, L, Li, T, Chan, JF, Budd, C, Mangelsdorf, DJ & Cummins, CL 2011, 'LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice', Journal of Clinical Investigation, vol. 121, no. 1, pp. 431-441. https://doi.org/10.1172/JCI41681
Patel, Rucha ; Patel, Monika ; Tsai, Ricky ; Lin, Vicky ; Bookout, Angie L. ; Zhang, Yuan ; Magomedova, Lilia ; Li, Tingting ; Chan, Jessica F. ; Budd, Conrad ; Mangelsdorf, David J. ; Cummins, Carolyn L. / LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 1. pp. 431-441.
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