Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cellular stress causes fatty liver disease in mice

09.12.2008
Study in mice shows direct link between disrupted protein folding and abnormal fat metabolism in the liver

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."

Jennifer Brown | EurekAlert!
Further information:
http://www.uiowa.edu

More articles from Life Sciences:

nachricht How brains surrender to sleep
23.06.2017 | IMP - Forschungsinstitut für Molekulare Pathologie GmbH

nachricht A new technique isolates neuronal activity during memory consolidation
22.06.2017 | Spanish National Research Council (CSIC)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>