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
The Mount Sinai Health System is an integrated health system committed to providing distinguished care, conducting transformative research, and advancing biomedical education. Structured around seven hospital campuses and a single medical school, the Health System has an extensive ambulatory network and a range of inpatient and outpatient services—from community-based facilities to tertiary and quaternary care.
The System includes approximately 7,100 primary and specialty care physicians; 12 joint-venture ambulatory surgery centers; more than 140 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. Physicians are affiliated with the renowned Icahn School of Medicine at Mount Sinai, which is ranked among the highest in the nation in National Institutes of Health funding per investigator. The Mount Sinai Hospital is in the "Honor Roll" of best hospitals in America, ranked No. 15 nationally in the 2016-2017 "Best Hospitals" issue of U.S. News & World Report. The Mount Sinai Hospital is also ranked as one of the nation's top 20 hospitals in Geriatrics, Gastroenterology/GI Surgery, Cardiology/Heart Surgery, Diabetes/Endocrinology, Nephrology, Neurology/Neurosurgery, and Ear, Nose & Throat, and is in the top 50 in four other specialties. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 10 nationally for Ophthalmology, while Mount Sinai Beth Israel, Mount Sinai St. Luke's, and Mount Sinai West are ranked regionally. Mount Sinai's Kravis Children's Hospital is ranked in seven out of ten pediatric specialties by U.S. News & World Report in "Best Children's Hospitals."