Why does one person’s liver fail while another’s doesn’t? Minerva’s research group seeks answers at the cellular level

Fatty liver disease is one of the greatest yet most invisible health challenges of our time, affecting an estimated one in three people worldwide. At the Minerva Foundation Institute for Medical Research, physician and researcher Panu Luukkonen, leader of the Fatty Liver Disease and Diabetes research group, is working with his team to uncover why this insidious disease progresses to dangerous liver cirrhosis in some individuals, while others are spared from the worst outcomes.

A researcher’s curiosity sparked by the root causes of public health diseases

Luukkonen’s path to becoming a researcher began during his time in medical school in Kuopio. During his studies, he realized that the underlying cause of major Finnish public health diseases, such as type 2 diabetes and cardiovascular disease, often stems from the same pathological process: insulin resistance.

– I became fascinated by the study of metabolic syndrome and insulin resistance, and along the way, I learned that the liver is the most central organ in the development of metabolic syndrome. A fatty liver is very strongly linked to metabolic disorders throughout the entire body, Luukkonen explains.

The desire to research a topic of great public health significance brought Luukkonen to Minerva in 2014, where he began his doctoral thesis in the research group of Professor Hannele Yki-Järvinen, a highly respected researcher in the field. After gaining international experience and expanding his expertise as a postdoctoral researcher at Yale University in the United States from 2019 to 2022, Luukkonen returned to Minerva. This time to take over the leadership of the research group. Luukkonen views his current role as his dream job:

– I am a reflective person by nature, and I feel that being a researcher is the best possible profession for me; there simply isn’t a better job. Of course, the daily life of a group leader involves more mentoring and administrative work, but I feel privileged to still be able to feed my scientific curiosity in the company of highly skilled and talented researchers.

Why does one person’s liver fail? Mitochondria under the microscope

A long-standing and strong area of expertise for the Fatty Liver Disease and Diabetes research group has been mapping lifestyle factors, such as diets high in sugar and fat, as well as genetic factors involved in fatty liver disease. Now, the group led by Luukkonen is actively exploring new scientific directions to solve a puzzling disparity: why does the disease progress to its most dangerous form, liver cirrhosis, in only a fraction of patients with a fatty liver?

The answer is currently being sought at the cellular level, more specifically within the cells’ powerplants: the mitochondria.

– We have found a strong lead suggesting that poor mitochondrial function in the liver predisposes a person to disease progression. We are now investigating from several different perspectives why the function of these organelles is disrupted in some people. We are exploring whether mitochondrial weakness is hereditary, how diet affects it, and whether mitochondria could serve as a potential target for new treatments in the future, Luukkonen outlines.

Healthy lifestyle is the most effective medicine – even for those with genetic risk

Even as science advances, the most effective tool for treating and preventing fatty liver disease is still found in lifestyle choices. Luukkonen emphasizes that the situation is never hopeless: the liver is an incredibly regenerative organ, and lifestyle changes begin to show results there within just a few days.

Abdominal obesity is the greatest risk factor for a fatty liver, but even minor weight loss yields significant results. A weight loss of just a few percent easily reduces fat, particularly from the liver region. With a weight loss of around 10%, it is already possible to reduce scar tissue, or fibrosis, that has developed in the liver. Regular exercise also improves liver health, even if no weight is lost. In addition to these measures, avoiding alcohol is a key way to protect against fatty liver disease.

Today, there is much talk about new weight-loss medications, such as GLP-1 receptor agonists. Luukkonen views them as a positive and effective aid when the disease is already advanced and the patient needs additional help, but he reminds us that lifestyle intervention will always remain the foundation of treatment.

What about genetics? The research group has extensively studied common genetic variants (such as PNPLA3, TM6SF2, and MBOAT7) that alter the liver’s fat metabolism and predispose individuals to a fatty liver. Luukkonen has reassuring news for those who carry these genetic variants in their family:

– These genes do not operate in a vacuum; they interact with lifestyle. If your lifestyle habits are healthy, genetic variants have very little impact. While those who carry these genetic changes are admittedly more sensitive to the adverse effects of a poor lifestyle, the flip side is that they also benefit the most from lifestyle improvements. Through your own choices, you can effectively reduce the risk carried in your DNA.