Understanding the role of CIDEB in hepatic lipid metabolism and the pathogenesis of NAFLD

在英国，肝病是增长最快的过早死亡原因之一。在英国和其他发达国家，肥胖和2型糖尿病的发病率迅速上升，导致非酒精性脂肪性肝病（NAFLD）。NAFLD患者的肝脏以脂肪沉积和随后的炎症为特征，少数患者会导致肝硬化和肝癌。NAFLD是一种很难识别的疾病，并且很少有准确的测试来判断一个人是否会在长期内患上肝脏疾病或癌症。目前还没有治疗方案，因为我们不明白为什么患者会发展为NAFLD或为什么他们会发展为肝脏疾病。为了更好地了解NAFLD，我们已经确定了NAFLD患者肝脏中的DNA突变，这些突变是由疾病引起的。我们在许多患者中发现了相同基因的突变，这表明这些突变对NAFLD的肝脏有益，并且具有这些突变的肝细胞比正常肝细胞存活得更好。NAFLD中最常发生突变的基因之一是CIDEB。我们对CIDEB及其正常功能知之甚少，也不知道为什么它会在NAFLD中发生突变。我们知道肝细胞处理脂肪的能力很重要。我们已经进行了一些实验，表明突变形式的CIDEB可以防止细胞获得过多的脂肪，这可能对NAFLD患者有保护作用。在这个研究计划中，我们的目标是找出：1)CIDEB如何正常发挥作用，帮助肝细胞处理脂肪。2) CIDEB突变如何影响这种正常功能。3) CIDEB突变是否有助于肝细胞在暴露于压力（如脂肪过多）时存活或更好地生长。4)小鼠体内的CIDEB突变是否会导致肝脏处理脂肪或糖的能力发生变化，就像我们在人类NAFLD患者中看到的那样。5)小鼠体内CIDEB突变是否有助于或阻碍NAFLD所致肝脏疾病的发展。为了实现这一目标，我们将在实验室研究肝细胞，以及它们在存在CIDEB突变时的行为。我们的大部分研究将涉及研究培养皿中生长的细胞，以及手术后取出的患病人类肝脏样本。我们的研究还将包括研究小鼠的肝细胞，因为这是研究肝细胞之间复杂联系的唯一方法，当它们在几个月内发展为NAFLD时。这项拟议的工作将在剑桥大学的两个专门研究代谢和肝脏疾病的实验室以及来自欧洲的合作者中进行，他们将各自带来特定的专业知识来研究CIDEB在肝脏疾病中的功能。如果我们能发现CIDEB如何正常发挥作用，以及它在NAFLD中如何变化，就有可能设计出针对CIDEB的药物。这些药物可以用来预防NAFLD或肝癌的发生。

Liver disease is one of the fastest rising causes of premature death in the UK. This is driven by a rapid rise in the rates of obesity and type 2 diabetes, that lead to non-alcoholic fatty liver disease (NAFLD), in the UK and other developed countries. The liver from patients with NAFLD is marked by fat deposition and subsequent inflammation, leading to cirrhosis and liver cancer in a minority. NAFLD is a condition that is hard to identify and has few accurate tests that can tell if a person will develop liver disease or cancer in the longer term. There are no treatment options, because we do not understand why patients develop NAFLD or why they progress to liver disease. To try and understand NAFLD better, we have identified DNA mutations in the liver of patients with NAFLD, that develop because of the disease. We identified mutations of the same genes in a number of patients, suggesting that these mutations are beneficial to the liver in NAFLD and that liver cells with these mutations survive better than normal liver cells. One of the genes that was frequently mutated in NAFLD was CIDEB.We know very little about CIDEB and how it functions normally, nor why it might be mutated in NAFLD. We do know that it is important in the ability of liver cells to handle fat. We have performed some experiments that show that the mutant forms of CIDEB prevent cells from acquiring too much fat, which may be protective if patients develop NAFLD.In this research proposal, we aim to find out:1) How CIDEB functions normally to help with liver cells to handle fat. 2) How mutations in CIDEB affect this normal function.3) Whether mutations of CIDEB help liver cells survive or grow better when exposed to stress, such as too much fat.4) Whether mutations of CIDEB in mice lead to changes in the ability of the liver to handle fats or sugars, such as we see in human patients with NAFLD. 5) Whether mutations of CIDEB in mice helps or hinders the development of liver disease caused by NAFLD.To achieve this, we will study liver cells in the laboratory and how they behave when CIDEB mutations are present. Much of our research will involve studying cells grown in a dish, as well as diseased human liver samples, which have been removed after surgery. Our research will also involve studying liver cells in mice, as this is the only way to study the complex links between liver cells, when they are developing NAFLD over the course of several months.This proposed work will be carried out in two laboratories at the University of Cambridge that specialise in the study of metabolism and liver disease, as well as collaborators from Europe, who will each bring specific expertise to study aspects of CIDEB function in liver disease.If we can find out how CIDEB functions normally and how this changes in NAFLD, it might be possible to design medicines that target CIDEB. These medicines could be used to prevent patients from developing NAFLD or liver cancer in the future.