B4447 - Damaging mutations in LXR uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver hea - 06/11/2023

B number: 
Principal applicant name: 
Kushala Abeysekera | University of Bristol (United Kingdom)
Dr Sam Lockhart
Title of project: 
Damaging mutations in LXR uncouple lipogenesis from hepatotoxicity and implicate hepatic cholesterol sensing in human liver hea
Proposal summary: 

We are interested in how metabolic dysfunction leads to liver disease. While it is well known that having a ‘fatty liver’ is a risk factor for liver inflammation and scarring – so-called cirrhosis, the specific mechanisms that drive this relationship are not well understood. Cholesterol, has a well described role in the development of heart disease and stroke, but it is actually increased in people with fatty liver disease – but if it is truly harmful and how it may cause harm is not clear.

In previous work, we have studied the role of a protein that has a key role in limiting cholesterol accumulation inside liver cells, LXRalpha. We have found that people who carry rare mutations in the DNA that tells the body how to make this protein have evidence of subtle liver damage despite actually seeming to be protected from accruing liver fat. We have also made a mouse model that has no functional LXRalpha and these mice develop severe liver injury with marked scarring whenever they are exposed to a fatty diet with cholesterol.

Together these findings provide evidence that this protein, and liver cholesterol metabolism generally, are important in maintaining liver health in humans. However, we have studied this in a large study called UK biobank, a study of older individuals who tend to be healthier than the general population and have mostly been studied at a single time point. Using Alspac, we want to understand if these findings are valid in a younger population and to characterise the dysfunctional LXRalpha on human liver health over time. We expect that replicating our findings in Alspac will demonstrate the robustness and generalisability of our findings and confirm the role of LXRalpha in maintaining human liver health.

Impact of research: 
This will guide therapeutic drug development to prevent liver injury. There is currently interest in developing LXR agonists to treat steatohepatitis, but this might be problematic due to pleiotropic effects of LXRalpha that the Cambridge group have evidenced in adults.
Date proposal received: 
Thursday, 26 October, 2023
Date proposal approved: 
Thursday, 2 November, 2023
Genetics, Metabolic health, lipid metabolism, liver disease , Metabolomics, Metabolic - metabolism