LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice
LXRβ is required for glucocorticoid-induced hyperglycemia and hepatosteatosis in mice
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DOI：
10.1172/jci41681
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发表时间：
2011-01-01
影响因子：
15.9
通讯作者：
Cummins, Carolyn L.
中科院分区：
文献类型：
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作者：
Patel, Rucha;Patel, Monika;Cummins, Carolyn L.
虽然糖皮质激素药物(如地塞米松)因其有效的抗炎作用而被广泛处方，但它会引起代谢综合征的不良副作用，包括高血糖、脂肪肝、胰岛素抵抗和II型糖尿病。肝x受体(Lxr)是核受体，它能对CHESTOL代谢物做出反应，并调节糖皮质激素靶基因亚群的表达，我们证明lxrβ是介导糖皮质激素的许多负面副作用所必需的，缺乏lxrβ(而不是lxrα)的小鼠对地塞米松诱导的高血糖、高胰岛素血症和肝脏脂肪变性具有抵抗力，但在体内对依赖地塞米松的免疫系统的抑制仍然敏感。LXRα/β基因敲除小鼠的肝脏和原代肝细胞中，地塞米松诱导的关键糖异生基因磷酸烯醇式丙酮酸羧激酶(PEPCK)的表达减少，糖皮质激素诱导的糖皮质激素受体重新募集到PEPCK启动子需要LXRβ。这些发现表明，通过选择性糖皮质激素受体反式激活的机制，设计更安全的糖皮质激素药物是一条新的途径。
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 chaesterol metabolites and regulate the expression of a subset of glucocorticoid target genes Here, we show LXR beta is required to mediate many of the negative side effects of glucocorticoids Mice lacking LXR beta (but not LXR alpha) were resistant to dexamethasone-induced hyperglycemia, hyperinsulinemia, and hepatic steatosis, but remained sensitive to dexamethasone-dependent repression of the immune system In vivo, LXR alpha/beta knockout mice demonstrated reduced dexamethasone-induced expression of the key lit patic gluconeogenic gene, phosphoenolpyruvate carboxykinase (PEPCK) In perfused liver and primary mouse hepatocytes, LXR beta 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