The Hepatoprotective Role of the Orphan Nuclear Receptor LXR

描述（由申请人提供）：肝脏X受体（LXRs），包括1和2亚型，在肝脏中高度表达，可以被天然和合成配体激活。以往对LXRs的研究主要集中在它们在胆固醇和脂质稳态和炎症中的作用。LXRs是否在抗内源性和外源性毒物的肝保护中起作用尚未得到充分探讨。对乙酰氨基酚（APAP）或泰诺（Tylenol）是一种非处方药物，是一种外源性毒性药物，过量服用是急性肝衰竭的主要原因。我们的初步结果表明，在肝脏中表达活化LXR1 （VP-LXR1）的转基因小鼠的APAP解毒酶表达增加，包括硫代转移酶SULT2A9和谷胱甘肽s转移酶（GSTs）。启动子分析表明，SULT2A9、GST M1和MRP2是LXR的转录靶点。我们还发现VP-LXR1转基因小鼠对APAP肝毒性具有更强的抗性。apap解毒转运体MRP4也可能受到LXR的阳性控制。我们假设LXRs通过转录激活APAP-解毒酶和/或转运体具有肝脏保护作用。一个可验证的预测是LXRs的激活将减轻APAP引起的肝毒性。由于炎症反应与APAP毒性有关，我们预计LXR的抗炎功能也可能有助于LXR的肝脏保护作用。利用LXR转基因、敲除和配体处理的野生型小鼠，我们提出：(1)构建LXR敲入小鼠，表达组成型激活的LXR1和LXR2。(2)确定LXRs的激活是否减轻APAP肝毒性。(3)确定LXRs调控鼠类和人apap解毒谷胱甘肽s -转移酶（GSTs）的分子基础。这些研究有望确立LXRs在保护外源性和内源性化学损伤方面的新功能。LXR对APAP的保护作用可能与报道的对异种受体妊娠X受体（PXR）和组成型雄烷受体（CAR）的致敏作用相反。希望选择性LXR激动剂的开发可能代表一种预防和治疗apap诱导的肝毒性的新策略。

DESCRIPTION (provided by applicant): The liver X receptors (LXRs), including the 1 and 2 isoforms, are highly expressed in the liver and can be activated by natural and synthetic ligands. Previous studies on LXRs have been focused on their role in cholesterol and lipid homeostasis and inflammation. Whether or not LXRs play a role in hepatoprotection against endo- and xenobiotic toxicants has not been fully explored. Acetaminophen (APAP) or Tylenol, an over-the-counter medication, is a xenobiotic toxicant whose overdose is the leading cause of acute liver failure. Our preliminary results showed that transgenic mice expressing the activated LXR1 (VP-LXR1) in the liver had an increased expression of APAP detoxifying enzymes, including the sulfotransferase SULT2A9 and glutathione S-transferases (GSTs). Promoter analysis suggested that SULT2A9, GST M1, and MRP2 are transcriptional targets of LXR. We also showed that the VP-LXR1 transgenic mice were more resistant to APAP hepatotoxicity. The APAP-detoxifying transporter MRP4 is also likely under the positive control of LXR. We hypothesize that LXRs have a hepatoprotective role by transcriptional activation of APAP- detoxifying enzymes and/or transporters. A testable prediction is that activation of LXRs will alleviate hepatotoxicity caused by APAP. Since inflammatory responses are involved in APAP toxicity, we anticipate that the anti-inflammatory function of LXR may also contribute to the hepatoprotective role of LXRs. By using the LXR transgenic, knockout and ligand-treated wild type mice, we propose: (1) To create LXR knock-in mice that bear the expression of constitutively activated LXR1 and LXR2. (2) To determine whether the activation of LXRs alleviates APAP hepatotoxicity. (3) To determine the molecular basis by which LXRs regulate the rodent and human APAP-detoxifying glutathione S-transferases (GSTs). These studies are expected to establish a novel function for LXRs in protecting xenobiotic and endobiotic chemical insults. The APAP protective role of LXR would be opposite to the sensitizing effects that have been reported for xenobiotic receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR). It is hoped that the development of selective LXR agonists may represent a novel strategy for the prevention and treatment of APAP-induced hepatotoxicity. Public Health Relevance: The liver X receptors (LXRs) are transcriptional factors highly expressed in the liver. The goal of this study is to determine whether LXRs play a hepatoprotective role in preventing toxicity from acetaminophen (APAP), whose overdose is the most common cause of clinical drug-related liver failures. It is hoped that the development of selective LXR agonists may represent a novel strategy for the prevention and treatment of APAP-induced liver toxicity.