New Pathway Found For Fatty Liver Disease
Fatty liver disease is the most common liver pathology in the western world, affecting up to 25 percent of adults in the United States and setting some of them up for future liver failure. Now, University of Michigan researchers describe their new understanding of how metabolic diseases such as fatty liver disease may develop.
The research was published online yesterday in the journal Developmental Cell, and recent papers in the journals Proceedings of the National Academy of Sciences and Journal of Clinical Investigation.
The work focuses on the stress-sensing pathways of cells and what might happen when they are disrupted by environmental factors, such as heavy alcohol use or high-fat diets.
Eventually, the findings may allow doctors to help patients stave off complications of fatty liver disease, diabetes and even neurodegenerative diseases such as Parkinson's.
“What we've come across is a new cellular pathway that might contribute to fatty liver disease and the complications associated with it,” says Thomas Rutkowski, Ph.D., the study's first author, who conducted the research while completing his postdoctoral work at the Howard Hughes Medical Institute (HHMI) at the University of Michigan, under the direction of Randal J. Kaufman, Ph.D.
Kaufman is a professor in the Department of Biological Chemistry at the U-M Medical School and an investigator with HHMI. Rutkowski is currently assistant professor of anatomy and cell biology at the University of Iowa Carver College of Medicine.
Chronic alcoholism and hepatitis C infection can cause fatty liver disease; it is also associated with diabetes and obesity. People with accumulated fat in the liver may not show symptoms at first, but over time it can lead to liver inflammation and injury, a condition called steatohepatitis. Complications of steatohepatitis include cirrhosis and liver failure, and they can shorten a person’s quality and length of life.
The research involved studying how three separate pathways in the unfolded protein response (UPR) protect cellular function in the endoplasmic reticulum (ER), the area of the cell where proteins begins their journey to the world outside.
Secreting proteins or inserting them into the cell membrane is how the cell communicates with the environment. These proteins are first synthesized in the ER, a network of tubes and sacs where these proteins “ fold” into their correct three-dimensional shapes before they reach the cell's surface.
If proteins fail to fold properly, they won’t be able to carry out their functions. Worse yet, they can form damaging protein aggregates such as the amyloid plaques that characterize the brains of Alzheimer’s disease patients. Changes or stresses outside the cell can result in abnormal folding inside the ER. If this happens, the cell adapts by initiating the unfolded protein response.
The UPR is a cell’s way to ensure its ability to secrete proteins is working properly. Its role is to turn on genes that help the ER properly fold proteins, akin to adding quality control inspectors in a factory. With these genes turned on, the cell is better equipped to handle the stress of protein folding problems in the ER. However, sometimes the stress can be too severe, overwhelming the UPR and leading to abnormal cellular function.
The finding of the link between fatty liver disease and ER stress was "a bit of serendipity," Rutkowski says.
Initially, Kaufman and his researchers set out to understand the basic mechanism by which cells sense that there is ER stress and respond and adapt to it.
“Any time the cell senses any stress, there are three p roteins -- ATF-6, IRE-1 and PERK -- whose job is to sense disruption in ER function,” Rutkowski says. “We wanted to understand what role they played in keeping the ER healthy.”