Dept. of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden.
Am J Physiol Endocrinol Metab. 2010 Feb;298(2):E167-78. doi: 10.1152/ajpendo.00184.2009. Epub 2009 Aug 18.
The two liver X receptors (LXRs), LXRalpha and LXRbeta, are transcriptional regulators of cholesterol, lipid, and glucose metabolism and are both activated by oxysterols. Impaired metabolism is linked with obesity, insulin resistance, and type 2-diabetes (T2D). In the present study, we aimed to delineate the specific roles of LXRalpha and -beta in metabolic processes. C57Bl/6 female mice were fed a normal or a high-fat diet (HFD) and metabolic responses in wild-type, LXRalpha(-/-), LXRbeta(-/-), and LXRalphabeta(-/-) mice were analyzed. Whole body fat and intramyocellular lipid contents were measured by nuclear magnetic resonance. Energy expenditure was measured in individual metabolic cages. Glucose, insulin, and pyruvate tolerance tests were performed and gene expression profiles analyzed by qPCR. We found that both LXRbeta(-/-) and LXRalphabeta(-/-) mice are resistant to HFD-induced obesity independently of the presence of high cholesterol. Using tolerance tests, we found that, on an HFD, LXRbeta(-/-) mice enhanced their endogenous glucose production and became highly insulin resistant, whereas LXRalpha(-/-) and LXRalphabeta(-/-) mice remained glucose tolerant and insulin sensitive. Gene expression profiling confirmed that LXRbeta is the regulator of lipogenic genes in visceral white adipose tissue (WAT) and muscle tissue and, surprisingly, that Ucp1 and Dio2 are not responsible for the protection against diet-induced obesity observed in LXRbeta(-/-) and LXRalphabeta(-/-) mice. LXRalpha is required for the control of cholesterol metabolism in the liver, while LXRbeta appears to be a major regulator of glucose homeostasis and energy utilization and of fat storage in muscle and WAT. We conclude that selective LXRbeta agonists would be novel pharmaceuticals in the treatment of T2D.
两种肝 X 受体 (LXRs)，LXRalpha 和 LXRbeta，是胆固醇、脂质和葡萄糖代谢的转录调节剂，均被氧化固醇激活。代谢受损与肥胖、胰岛素抵抗和 2 型糖尿病 (T2D) 有关。在本研究中，我们旨在描绘 LXRalpha 和 -beta 在代谢过程中的特定作用。用正常或高脂肪饮食 (HFD) 喂养 C57Bl/6 雌性小鼠，并分析野生型、LXRalpha(-/-)、LXRbeta(-/-)和 LXRalphabeta(-/-)小鼠的代谢反应。通过核磁共振测量全身脂肪和肌内脂肪含量。在个体代谢笼中测量能量消耗。进行葡萄糖、胰岛素和丙酮酸耐量试验，并通过 qPCR 分析基因表达谱。我们发现，LXRbeta(-/-)和 LXRalphabeta(-/-)小鼠在不伴有高胆固醇的情况下均能抵抗 HFD 诱导的肥胖。使用耐量试验，我们发现，在 HFD 下，LXRbeta(-/-)小鼠增强了内源性葡萄糖产生，并且对胰岛素高度抵抗，而 LXRalpha(-/-)和 LXRalphabeta(-/-)小鼠仍然对葡萄糖耐受且胰岛素敏感。基因表达谱分析证实，LXRbeta 是内脏白色脂肪组织 (WAT) 和肌肉组织中脂肪生成基因的调节剂，令人惊讶的是，Ucp1 和 Dio2 不是导致 LXRbeta(-/-)和 LXRalphabeta(-/-)小鼠对饮食诱导的肥胖的保护作用的原因。LXRalpha 是控制肝脏胆固醇代谢所必需的，而 LXRbeta 似乎是葡萄糖稳态和能量利用以及肌肉和 WAT 脂肪储存的主要调节剂。我们得出结论，选择性 LXRbeta 激动剂将成为治疗 T2D 的新型药物。
