Experts Identify Key Protein Factor Linked to Alcoholic Fatty Liver Disease
A new study has identified a causative link between a key cell stress response pathway and alcoholic liver disease advancing understanding of how this disease develops. Researchers from the Icahn School of Medicine at Mount Sinai have discovered that by blocking a protein called ATF6 (or activating transcription factor) helped prevent alcohol-induced fatty liver disease while overexpression of the protein caused the disease to develop in zebrafish. These findings demonstrate the first, clear and causative link between a key unfolded protein response and fatty liver disease. The study results were published today in the journal PLoS Genetics.
Until now little has been understood about the role of ATF6 in regulating liver metabolism or how fatty liver disease develops. “When alcohol is consumed, the cellular stress that is caused activates a pathway called the unfolded protein response,” says lead author Kirsten Sadler, PhD, Associate Professor in the Division of Liver Diseases in the Samuel Bronfman Department of Medicine and in the Department of Developmental and Regenerative Biology at the Icahn School of Medicine at Mount Sinai. “This deficient protein response in liver cells often leads to the development of a fatty liver.”
Long held clinical observations have found that alcoholics frequently suffer from complications, such as bleeding, attributed to deficiencies in the proteins. “By identifying a link between the unfolded protein response and metabolic disorders, this study is among the first to make a clear, direct and mechanistic connection between liver cell stress (caused by alcohol), activation of a critical pathway in the cell (the unfolded protein response), and the development of fatty liver disease,” added Sadler.
To mimic the effects of a binge drink, researchers bathed young zebrafish in alcohol. The effect of the alcohol on the liver of the zebrafish was similar to the effect on a human liver, and included compromised liver cell function and a fatty liver. The secretion of cell proteins was controlled by the presence of ATF6 and induced when cells were stressed by excessive alcohol exposure. The activation of ATF6 on its own, in the absence of stress, was sufficient to cause fatty liver disease in zebrafish while blocking ATF6 prevented a fatty liver from developing.
Although fatty liver is caused by alcohol, it can also be triggered by obesity and type II diabetes. “The discovery of the role of ATF6 in the development of fatty liver disease may shed light on other causes of this disease,” says Sadler. “Future studies are needed to identify ways to prevent cell stress caused by alcohol and other conditions, possibly leading to therapeutic options to treat this disease.”
About the Mount Sinai Health System
Mount Sinai Health System is one of the nation’s leading integrated academic health systems and one of the largest in the New York metropolitan area. Its comprehensive system includes seven hospitals, more than 400 outpatient practices, over 600 research and clinical laboratories, the Icahn School of Medicine at Mount Sinai, the Graduate School of Biomedical Sciences, and the Mount Sinai Phillips School of Nursing. Together, the Health System comprises approximately 48,000 employees, more than 9,000 physicians, and 8,600 nurses.
As a leading learning health system, Mount Sinai combines clinical expertise with scientific discovery to improve patient care while training the next generation of health care and biomedical leaders. The Health System provides care across every stage of life, from prenatal care through geriatrics, while advancing personalized medicine through artificial intelligence, data science, and biomedical research.
Mount Sinai is consistently recognized among the nation’s leading academic health systems for patient care, research, and education. The Mount Sinai Hospital is ranked No. 1 in New York by Newsweek and No. 5 on the magazine’s World’s Best Hospitals list. The Icahn School of Medicine at Mount Sinai ranks No. 11 among U.S. medical schools and No. 1 among freestanding medical schools for National Institutes of Health funding, reflecting the strength of its scientific enterprise and leadership in biomedical research.
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