In a study on mice, researchers at University of Iowa and University of Michigan have found that disrupted protein folding may lead to fatty liver disease, a condition that causes fat to accumulate in the liver.
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, is the first to demonstrate a direct link between this critical cellular housekeeping process and abnormal fat metabolism.
AdvertisementThe results of the study may pave the way for understanding and perhaps treating fatty liver disease. While 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.
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.
For determining how cells adapt to stress, the researchers created mice that were missing one component of the UPR. Usually, 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. Besides, the team found that protein misfolding caused fatty liver in mice with the mutation.
"We did not set out to understand fatty liver disease. 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," said Rutkowski.
He added: "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."
Following up on the result, the researchers 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.
The 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.
After further analysis of the mice models, scientists could identify some of the genes that connect prolonged ER stress with faulty fat metabolism in the liver. Particularly, 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.
The scientists speculated that if the 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. 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," said Rutkowski.
The study was published in the latest issue of the journal Developmental Cell.
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