Baranowski M
Department of Physiology, Medical University of Bialystok, Bialystok, Poland.
J Physiol Pharmacol. 2008 Dec;59 Suppl 7:31-55.
Liver X receptors (LXRs) are ligand-activated transcription factors of the nuclear receptor superfamily. There are two LXR isoforms termed alpha and beta which upon activation form heterodimers with retinoid X receptor and bind to LXR response element found in the promoter region of the target genes. Their endogenous agonists include a variety of oxidized cholesterol derivatives referred to as oxysterols. In the recent years LXRs have been characterized as key transcriptional regulators of lipid and carbohydrate metabolism. LXRs were shown to function as sterol sensors protecting the cells from cholesterol overload by stimulating reverse cholesterol transport and activating its conversion to bile acids in the liver. This finding led to identification of LXR agonists as potent antiatherogenic agents in rodent models of atherosclerosis. However, first-generation LXR activators were also shown to stimulate lipogenesis via sterol regulatory element binding protein-1c leading to liver steatosis and hypertriglyceridemia. Despite their lipogenic action, LXR agonists possess antidiabetic properties. LXR activation normalizes glycemia and improves insulin sensitivity in rodent models of type 2 diabetes and insulin resistance. Antidiabetic action of LXR agonists is thought to result predominantly from suppression of hepatic gluconeogenesis. However, recent studies suggest that LXR activation may also enhance peripheral glucose uptake. The purpose of this review is to summarize the present state of knowledge on the physiological and pathophysiological implications of LXRs with the special consideration of their role in lipid and carbohydrate metabolism and associated diseases.
肝脏X受体（LXRs）是核受体超家族中受配体激活的转录因子。有两种LXR亚型，即α和β，激活后它们与视黄酸X受体形成异二聚体，并与靶基因启动子区域中发现的LXR反应元件结合。它们的内源性激动剂包括多种被称为氧化固醇的氧化胆固醇衍生物。近年来，LXRs已被确定为脂质和碳水化合物代谢的关键转录调节因子。LXRs被证明可作为固醇传感器，通过刺激胆固醇逆向转运并激活其在肝脏中转化为胆汁酸，保护细胞免受胆固醇过载的影响。这一发现导致在动脉粥样硬化的啮齿动物模型中，LXR激动剂被确定为有效的抗动脉粥样硬化药物。然而，第一代LXR激活剂也被证明可通过固醇调节元件结合蛋白-1c刺激脂肪生成，导致肝脂肪变性和高甘油三酯血症。尽管具有脂肪生成作用，LXR激动剂仍具有抗糖尿病特性。在2型糖尿病和胰岛素抵抗的啮齿动物模型中，LXR激活可使血糖正常化并提高胰岛素敏感性。LXR激动剂的抗糖尿病作用被认为主要源于对肝糖异生的抑制。然而，最近的研究表明，LXR激活也可能增强外周葡萄糖摄取。本综述的目的是总结关于LXRs生理和病理生理意义的现有知识，特别考虑它们在脂质和碳水化合物代谢及相关疾病中的作用。
