Role of nuclear receptors in hepatic injury and fibrogenesis

慢性肝病是世界范围内死亡和健康状况不佳的主要原因。几种常见的肝脏疾病，如B型肝炎，丙型肝炎和非酒精性脂肪性肝炎（非酒精性脂肪肝），能够引起长期的肝损伤。无论损伤的原因如何，肝脏对慢性损伤的反应方式非常狭窄。其中最重要和最阴险的是肝纤维化（瘢痕形成），如果损伤过程足够强烈和持续，则其沿着肝再生，最终导致肝硬化。肝硬化是肝脏疾病的几种不良并发症的前兆，最值得注意的是原发性肝癌（也称为肝细胞瘤），肝功能衰竭和严重的肠道出血。因此，毫不奇怪，控制肝损伤和预防肝硬化的有效策略被称为肝脏研究的圣杯。到目前为止，唯一能显著改善慢性肝病患者预后的疗法是那些停止或消除损伤原因的疗法。不幸的是，在许多情况下，仍然无法消除或有效治疗受伤的原因。正因为如此，人们对可能有利地改变肝脏对损伤的反应的疗法，特别是那些可能延缓或抑制瘢痕形成和预防肝硬化的疗法产生了浓厚的兴趣。核受体是控制身体代谢的许多方面的传感器，特别是胆固醇和脂肪的代谢。最近，我们和其他人的工作表明，一些核受体可能在肝脏如何应对损伤以及肝脏是否会瘢痕化并发展为肝硬化方面发挥重要作用。我们的实验将确定是否如此，以及可能涉及的几种核受体中哪些是重要的。然后，我们将扩展这些研究，看看激活这些受体的药物是否会改善或预防严重的肝脏疾病。

Chronic liver disease is a major cause of death and ill health on a word-wide scale. Several common liver diseases, such as hepatitis B, hepatitis C and non-alcoholic steatohepatitis (fatty liver disease not due to alcohol), are capable of causing protracted liver damage. Irrespective of the cause of injury, the liver has a very narrow way of responding to chronic damage. The most important and insidious of these is hepatic fibrosis (scarring), which, along with liver regeneration, eventually leads to cirrhosis if the injurious process is sufficiently intense and sustained. Liver cirrhosis is the precursor to several undesirable complications of liver disease, most notably primary liver cancer (also called hepatoma), liver failure and severe bleeding from the gut. Therefore, it is not surprising that effective strategies to control liver injury and prevent cirrhosis have been called the holy grail of liver research. To date the only therapies for substantially improving the outcome of patients with chronic liver disease are those that halt or remove the cause of injury. Unfortunately, in many cases it is still not possible to remove or effectively treat the cause of injury. Because of this there is intense interest in therapies that might favourably alter the response of the liver to injury and especially in those that may retard or inhibit scarring and prevent cirrhosis. Nuclear receptors are sensors that control many aspects of the body's metabolism, especially the metabolism of cholesterol and fat. Recently, our work and that of others has suggested that some nuclear receptors may play a vital role in how the liver responds to damage and whether the liver will the scar and move on to cirrhosis. Our experiments will determine if this is so, and which of the several nuclear receptors likely to be involved are the important ones. We will then extend these studies to see if drugs that activate these receptors will improve or prevent severe liver disease.