A University of Iowa researcher and colleagues at the University of Michigan have discovered a direct link between disruption of a critical cellular housekeeping process and fatty liver disease, a condition that causes fat to accumulate in the liver.

The findings, published in the Dec. 9 issue of the journal Developmental Cell, might open new avenues for understanding and perhaps treating fatty liver disease, which is the most common form of liver disease in the Western world and may affect as many as one in three American adults. Although fatty liver itself does not necessarily cause illness, it is associated with serious conditions like diabetes, metabolic syndrome, cirrhosis of the liver and liver failure.

The study, led by Tom Rutkowski, Ph.D., assistant professor of anatomy and cell biology at the UI Roy J. and Lucille A. Carver College of Medicine, and Randal Kaufman, Ph.D., professor of biological chemistry and internal medicine at the University of Michigan Medical School, shows that disrupted protein folding causes fatty liver in mice. The finding is the first to demonstrate a direct link between this form of cellular stress and abnormal fat metabolism.

Protein folding, which occurs in a cellular compartment called the endoplasmic reticulum (ER), is a vital cellular process because proteins must be correctly folded into defined three-dimensional shapes in order to function. Unfolded or misfolded proteins are a sign of cellular stress and can cause serious problems -- misfolded proteins cause amyloid plaques found in Alzheimer's disease. Cells rely on a very sensitive system known as the unfolded protein response (UPR) to guard against the cellular stress caused by protein folding problems.

To investigate how cells adapt to stress, the researchers created mice that were missing one component of the UPR. Under normal conditions, mice with the genetic mutation looked and behaved normally. However, the mutated mice were much less able to cope with cellular stress caused by disrupted protein folding than wild-type mice. In addition, the team found that protein misfolding caused fatty liver in mice with the mutation.

"We did not set out to understand fatty liver disease," said Rutkowski, who was a postdoctoral researcher in Kaufman's University of Michigan lab when the study was done. "We were really trying to understand the basic biology of how cells respond to stress, and through our approach to that fundamental question we were able to identify a connection to a condition that is of enormous importance to human health.

"When we realized that our experiments to investigate protein folding abnormalities were producing fatty liver disease as a consequence, it tied in with previous circumstantial evidence suggesting that ER stress might be involved in the liver's role in fat metabolism," he added.

The researchers followed up on the result and found that mice also developed fatty liver if their ability to fold proteins in the ER was genetically impaired, even when the UPR was functionally intact. This result suggested that the UPR is able to protect the liver against ER stress to a certain degree, but that fatty liver will result when the stress is too severe.

Further analysis of the mice models identified some of the genes that connect prolonged ER stress with faulty fat metabolism in the liver. In particular, the team found that unresolved ER stress leads to persistent expression of a gene called CHOP and that leads to changes in expression of fat metabolism genes. Mice with no CHOP were partially protected from fatty liver.

The results suggest that it is not disruption of a specific protein that caused fatty liver, but rather anything that perturbs the ER's ability to fold proteins correctly that is important. If this finding holds true for fatty liver disease in humans, therapies aimed at improving protein folding in the ER, or inhibiting CHOP, could help treat the condition.

"Our study does prove that perturbing protein folding can lead to fatty liver," Rutkowski said. "The next step is to investigate whether real physiological stresses like chronic alcohol consumption, obesity and viral infection also lead to fatty liver disease through protein folding problems in the ER."

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In addition to Rutkowski and Kaufman, who also is a Howard Hughes Medical Institute investigator, key members of the research team included Jun Wu, Ph.D., who was a graduate student at University of Michigan Medical Center, and Mahmood Hussain, Ph.D., at State University of New York Downstate Medical Center. Researchers from the University of Michigan Medical Center; the University of Washington, Seattle, Wash.; and Wayne State University, Detroit, Mich., also were involved in the study.

The study was funded in part by the National Institutes of Health