A research discovery from the Storr Liver Centre at the Westmead Institute for Medical Research in Sydney has identified why lean people with metabolic dysfunction-associated fatty liver disease (MAFLD) have higher mortality than their non-lean counterparts.
MAFLD is diagnosed when there is excessive fat build-up in the liver, along with other metabolic risk factors. The Westmead research finding provides a new drug target for the development of potentially lifesaving treatments, as well as the potential to increase early detection.
MAFLD affects up to a third of the global population, and is the leading cause of end-stage liver disease, liver cancer and liver transplantation. In Australia, the prevalence of MAFLD has been reported to be 20-30% and is the most common liver disease. But even though it is typically associated with excess weight, obesity and type-2 diabetes, around one fifth of people with MAFLD are considered to be lean, and can–counterintuitively–actually be worse.
Sydney University PhD student Mohammad Alarabi is a co-author of the study, published recently in Hepatology International. He said, “Despite being healthier overall than their overweight or obese counterparts, lean people with MAFLD have a worse long-term prognosis. We set out to understand the mechanisms that cause this seemingly contradictory outcome.”
The research team focused their efforts on telomeres. These are protective structures found on the end of chromosomes. Instead of coding for genetic information like the rest of the chromosome, telomeres act like protective caps. In a way, they are like the plastic-sheathed ends of shoelaces, preventing damage and unravelling. “Telomeres protect the end of a chromosome from becoming frayed and tangled,” Mohammad Alarabi explained.
“Each time a cell divides, some of the telomeres get cut off. Eventually, the telomeres become so short that the cell dies.” Thus telomeres tend to get shorter with age, and the shortening of telomeres is associated with increased morbidity and mortality in several diseases.
The Westmead study hypothesised that telomere loss increases in times of substantially higher energy demands or metabolic stress on the body. In the long term, this could lead to increased cell death and poorer health outcomes for the affected individual. In the study, the research team demonstrated that growth/differentiation factor-15 (GDF-15), a protein that helps to regulate a cell’s response to injury, is notably reduced in lean individuals with MAFLD.
As the body’s cells try to adapt to this reduction in GDF-15, it results in an increase in molecules known as endogenous reactive oxygen species (ROS). An increase in ROS can cause damage to telomeres, sometimes to such an extent that the containing cell dies.
…many lean individuals are diagnosed with MAFLD much later than their non-lean counterparts which results in delayed treatment.
“It is the combination of a decrease in GDF-15 and increase in ROS that leads to a more rapid loss of telomeres,” explained Mohammad Alarabi. “We have been able to demonstrate that the shortening of telomeres can, in part, explain the increased mortality of lean individuals with MAFLD. We say “in part” because there is another factor that we believe has an impact on mortality rates.
“As the name suggests, ‘fatty liver’ is usually associated with excess weight and obesity. Many health professionals do not consider that a lean person potentially has a ‘fatty liver’. This means that many lean individuals are diagnosed with MAFLD much later than their non-lean counterparts, which results in delayed treatment. This could also partially explain the increased mortality of lean individuals with MAFLD.”
The next step is to look for treatments that could stop the increase in ROS, reducing telomere loss and increasing survival rates for lean people with MAFLD, which the Westmead research team is now doing. Alarabi noted that they “hope to develop a biomarker that could identify increased ROS, and improve early detection of MAFLD in lean individuals.”
Last updated 28 November 2024
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