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

了解 CIDEB 在肝脏脂质代谢中的作用以及 NAFLD 的发病机制

基本信息

批准号：
MR/X00970X/1
负责人：
Matthew Hoare
金额：
$ 129.34万
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2023
资助国家：
英国
起止时间：
2023 至无数据
项目状态：
未结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FX00970X%2F1
关键词：
Understanding role CIDEB hepatic lipid

项目摘要

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.

肝病是英国过早死亡上升最快的原因之一。这是由英国和其他发达国家肥胖和 2 型糖尿病发病率迅速上升推动的，肥胖和 2 型糖尿病会导致非酒精性脂肪肝 (NAFLD)。 NAFLD 患者的肝脏以脂肪沉积和随后的炎症为特征，导致少数人出现肝硬化和肝癌。 NAFLD 是一种很难识别的疾病，并且很少有准确的测试可以判断一个人长期是否会患上肝病或癌症。没有治疗选择，因为我们不明白患者为何会发展为 NAFLD 或为何会进展为肝病。为了更好地理解 NAFLD，我们在 NAFLD 患者的肝脏中发现了因该疾病而产生的 DNA 突变。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 患者的肝脏有益，并且具有这些突变的肝细胞比正常肝细胞存活得更好。 CIDEB 是 NAFLD 中经常突变的基因之一。我们对 CIDEB 及其正常功能知之甚少，也不知道它为什么会在 NAFLD 中发生突变。我们确实知道它对于肝细胞处理脂肪的能力很重要。我们进行了一些实验，表明 CIDEB 的突变形式可以防止细胞获得过多的脂肪，这对于患者患有 NAFLD 可能具有保护作用。在这项研究计划中，我们的目标是找出：1) CIDEB 的正常功能如何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压力（例如过多的脂肪）下生存或更好地生长。4) 小鼠中 CIDEB 突变是否会导致肝细胞能力发生变化肝脏处理脂肪或糖，就像我们在患有 NAFLD 的人类患者中看到的那样。 5）小鼠中CIDEB突变是否有助于或阻碍NAFLD引起的肝病的发展。为了实现这一目标，我们将在实验室中研究肝细胞以及当CIDEB突变存在时它们的行为。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。我们的研究还将涉及研究小鼠的肝细胞，因为这是研究肝细胞在几个月内发展为 NAFLD 时肝细胞之间复杂联系的唯一方法。这项拟议的工作将在两个实验室中进行专门研究代谢和肝病的剑桥大学以及来自欧洲的合作者，他们将各自带来特定的专业知识来研究 CIDEB 在肝病中的功能。如果我们能找出 CIDEB 的正常功能以及它如何变化在 NAFLD 中，可能是设计针对 CIDEB 的药物成为可能。这些药物将来可用于预防患者患上 NAFLD 或肝癌。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The senescent secretome drives PLVAP expression in cultured human hepatic endothelial cells to promote monocyte transmigration.

DOI：
10.1016/j.isci.2023.107966
发表时间：
2023-10-20
期刊：
ISCIENCE
影响因子：
5.8
作者：
Wilkinson, Alex L.;Hulme, Samuel;Kennedy, James I.;Mann, Emily R.;Horn, Paul;Shepherd, Emma L.;Yin, Kelvin;Zaki, Marco Y. W.;Hardisty, Gareth;Lu, Wei-Yu;Rantakari, Pia;Adams, David H.;Salmi, Marko;Hoare, Matthew;Patten, Daniel A.;Shetty, Shishir
通讯作者：
Shetty, Shishir

Mouse models of hepatocyte biology - Known unknowns.

肝细胞生物学的小鼠模型 - 已知的未知数。