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New Insights into Non-Alcoholic Fatty Liver Disease Could Lead to First Treatment

In a groundbreaking study, researchers at the University of Virginia School of Medicine have uncovered a crucial trigger for non-alcoholic fatty liver disease, a mysterious condition that causes the liver to accumulate fat without any clear explanation. This discovery sheds light on the disease’s causes, especially in younger individuals, and could potentially lead to the development of the first-ever treatment for the world’s most common liver disease.

The researchers have identified that the formation of wrinkles in the nuclear lamina, which houses our DNA, is the culprit. Previous studies conducted by the same team had already established the potential involvement of these wrinkly cellular nuclei in metabolic diseases such as diabetes, fatty liver disease, and even aging. The new findings support these observations and open doors for targeted treatments that could potentially stop the development of non-alcoholic fatty liver disease and even slow down or reverse the aging process.

Dr. Anna Mae Diehl, a hepatologist, and liver disease specialist at Duke University, commented on the significance of the researchers’ discovery, saying, “This is an important discovery that could have broad implications for treating fatty liver disease, including the significant proportion of individuals with this disease who are young and seemingly healthy.”

Non-alcoholic fatty liver disease is widespread among heavy alcohol drinkers, but the disease can also occur in those who consume little to no alcohol, particularly older people and those with type 2 diabetes. The disease affects approximately 40% of people over the age of 70. In most cases, people with fatty liver disease do not experience any symptoms, but for some, it can cause fatigue, weakness, and abdominal pain, which can decrease their quality of life. Unfortunately, there is no cure for the disease.

Medical professionals have been struggling to understand what triggers non-alcoholic fatty liver disease, but the latest discovery by the UVA researchers indicates that malfunctions may occur within the “hard drives” of our cells, which contain the operating instructions for the cells. These changes start in the cell nucleus, where our chromosomes are stored, and alter the activity of certain genes that ultimately lead to fat accumulation in the liver.

The new research reveals that the fault lies in the lamina, a part of the nucleus that acts as a tether between the nuclear membrane and the genetic material within, known as chromatin. The formation of wrinkles in the lamina alters the activity of genes that control fat storage. This hyperactivity of genes leads to excessive fat accumulation in the liver, resulting in non-alcoholic fatty liver disease.

To validate their findings, the researchers examined liver cells obtained from younger human patients between the ages of 21 and 51, who were suffering from non-alcoholic fatty liver disease. As anticipated, the scientists found wrinkly lamina in the liver cells, which explains why the disease can occur in people of any age, making it easier to identify those at risk.

By targeting the harmful changes in the lamina, the researchers could develop new ways to treat or even prevent non-alcoholic fatty liver disease, as well as other metabolic diseases and aging. Dr. Bochkis, the lead author of the study, has suggested that scientists could use custom-tailored viruses to deliver different lamin proteins to the liver to smooth the membranes’ surfaces and restore the cells to proper function. The findings of the study have been published in the scientific journal Genome Research.

Dr. Bochkis commented on the importance of the discovery, stating that “Currently, there is no treatment for non-alcoholic fatty liver disease and no method to stratify the patients. 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 research team consisted of Xiaolong Wei, Megan A. Murphy, Nihal A. Reddy, Yi Hao, Megan A. Murphy, Nihal A. Reddy, Yi Hao, Taylor G. Eggertsen, Jeffrey J. Saucerman and Bochkis. Eggertsen and Saucerman are part of UVA’s Department of Biomedical Engineering, a joint program of the School of Medicine and School of Engineering.


University of Virginia Health System

Journal reference:

Wei, X., et al. (2022) Redistribution of lamina-associated domains reshapes binding of pioneer factor FOXA2 in development of nonalcoholic fatty liver disease. Genome Research. doi.org/10.1101/gr.277149.122.