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

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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.