UVA Health: 'Our findings could lead to novel treatments aimed at restoring the function of the nuclear lamina'

Significant advancement was achieved by scientists from the School of Medicine in comprehending the underlying mechanisms of non-alcoholic fatty liver disease, a common condition where fat builds up in the liver. 

Their research indicates that the formation of wrinkles within cellular nuclei may play a crucial role in initiating this disease, offering valuable insights into its occurrence among younger individuals and potentially leading to the development of the first-ever treatment for this widespread liver disorder. 

The breakthrough not only enhances our understanding of fatty liver disease but also holds the potential for addressing other metabolic disorders and even the aging process.

The study provides valuable insights into the occurrence of the disease in younger individuals and has the potential to lead to the development of the first-ever treatment for the most prevalent liver disease globally. 

Dr. Irina M. Bochkis, a senior researcher from UVA's Department of Pharmacology, identifies the formation of wrinkles in the cellular compartment containing our DNA as the primary trigger for non-alcoholic fatty liver disease. 

Previous research conducted by UVA scientists had already indicated the possible involvement of these wrinkled cellular nuclei in common metabolic disorders such as diabetes and fatty liver disease, as well as the aging process itself. 

The latest findings further support these conclusions and hold promise for targeted treatments aimed at addressing wrinkles, stopping fatty liver disease, and potentially slowing down or reversing the aging process.

"We found a common mechanism involving the nucleus and the nuclear lamina that leads to fat accumulation in the liver in aged individuals and younger people with non-alcoholic fatty liver disease," Dr. Bochkis said. 

"Our findings could lead to novel treatments aimed at restoring the function of the nuclear lamina to control aberrant genes and reverse fatty liver in young patients with non-alcoholic fatty liver disease or aged individuals." 

Non-alcoholic fatty liver disease is commonly associated with heavy alcohol consumption, as the excess fat stored in the liver serves as a warning sign of alcohol abuse. 

However, the disease also affects individuals who consume little or no alcohol, particularly older people and those with type 2 diabetes. Remarkably, approximately 40% of individuals over the age of 70 have this condition. 

While many people with fatty liver disease experience no symptoms and may be unaware of their condition, others suffer from weakness, fatigue, and abdominal pain, which significantly diminishes their quality of life. Unfortunately, there is currently no treatment available for the disease.

Understanding the triggers of non-alcoholic fatty liver disease has proven challenging for doctors, but UVA's groundbreaking discovery suggests that malfunctions within the "hard drives" that contain the cellular operating instructions may play a role. 

These changes originate within the cell nucleus, where chromosomes are stored, and impact the activity of specific genes, ultimately leading to the accumulation of fat in the liver. The new research indicates that the root cause lies within a segment of the nucleus called the lamina. 

The lamina acts as a tether between the nuclear membrane and the genetic material known as chromatin. The formation of wrinkles in the lamina, as discovered by Bochkis and her team, affects the activity of genes responsible for fat storage. 

When these genes become hyperactive, excess fats accumulate in the liver, resulting in non-alcoholic fatty liver disease.

To confirm their findings, the researchers examined liver cells obtained from younger patients aged 21-51 with non-alcoholic fatty liver disease. As anticipated, the scientists observed wrinkly lamina in these cells. 

This discovery helps explain why the disease can affect individuals of any age and may prove useful in identifying those at risk. By targeting the detrimental changes in the lamina, researchers could potentially develop interventions to treat or even prevent non-alcoholic fatty liver disease, along with other metabolic disorders and the aging process itself. 

For instance, scientists might explore the use of customized viruses to deliver different lamin proteins to the liver, smoothing the surfaces of the membranes and restoring cells to their proper function. 

"Currently, there is no treatment for non-alcoholic fatty liver disease and no method to stratify the patients," Dr. Bochkis said. "Our findings could lead to improved stratification and a novel treatment without side effects, where restoring the lamina function returns the cell to a healthy state with appropriate gene expression."

The scientists' findings have been published in the scientific journal Genome Research. The research team included Xiaolong Wei, Megan A. Murphy, Nihal A. Reddy, Yi Hao, Taylor G. Eggertsen, Jeffrey J. Saucerman, and Dr. Irina M. Bochkis. Eggertsen and Saucerman are affiliated with UVA's Department of Biomedical Engineering, a joint program of the School of Medicine and School of Engineering. 

The researchers disclosed no financial interests related to the study. The work received support from the National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases through grant R01 DK121059.