Mysterious molecule could trigger fatty liver disease

Researchers at the Medical University of South Carolina have identified a little-known molecule as a suspect behind the onset of liver disease. The researchers found that the mysterious molecule causes problems inside liver cells that try to fold proteins into forms that the body can use.   

The cell's response to unfolded or misfolded proteins could be a cause, rather than a consequence, of metabolic disorders, report MUSC researchers in an article published in the journal Nature Structural & Molecular Biology. 

Before the molecule behind this process was uncovered, it was not known whether unfolded proteins caused problems in the liver, or if problems in the liver caused a buildup of too many unfolded proteins. Because of this study, now there is proof that problems with protein folding can be a cause of liver problems, according to Zihai Li, M.D., Ph.D., chair of the Department of Microbiology and Immunology at the MUSC Hollings Cancer Center and principal investigator on the project. Feng Hong, M.D., Ph.D., in the Department of Microbiology and Immunology, is the first author of the paper. 

Li said the unfolded protein response in the cell plays important roles in aging and in many diseases such as cancer, diabetes and neurodegenerative disease. “Our study has now identified a key player. Like everthing else in life, if you find a culprit, you can do something about it. It opens up an enormous opportunity for research as well as finding a new treatment for these diseases.”

Why this is important is that all of the body’s cells must make proteins and other molecules in order to keep the metabolism running. First, proteins are made in long strands, and then they must be folded into their final shapes that the body can use as building materials or fuel. Fortunately, if a protein is unfolded or folded the wrong way at first, cells have an emergency brake called the unfolded protein response that can fold it the right way. 

The cell employs a supervisor protein, rather like a supervisor on a factory floor, to alert three main signals inside the cell when such proteins are found. Those signals activate the unfolded protein response and the cell then refolds or discards the defective protein.

There is a wrinkle, though.

When too many proteins have been folded wrong or are unfolded, the emergency brake can fail. In those cases, many cells can shut down and a whole organ can develop problems with metabolism. This is very important in the liver, which breaks down most of the fuel needed to keep the body running. In stressed liver cells, fats can build up to the point where a person develops non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease is the build up of extra fat in liver cells that is not caused by alcohol. It affects up to 25 percent of people in the U.S.

Researchers found that it is during this process that the mysterious molecule contributes to the problem. Li said before this, no one knew the mysterious molecule’s exact job in the cell. The molecule, which is called CNPY2, is known as a “canopy protein.” CNPY2 is thought to regulate signaling molecules on the surface of cells. To start, Li and his group removed the canopy protein from some mice and compared them to normal mice. Although the rodents were slightly smaller than normal mice, they were otherwise healthy. 

The researchers then fed the mice a high-fat diet for several weeks. Those that did not have the canopy protein were healthy, but normal mice with the canopy protein began to store too much fat in their livers. This was an early sign of non-alcoholic fatty liver disease, the same disease that can develop in people who eat a high-fat diet. 

Next the researchers looked even closer. Using experiments that are designed to see if two molecules can bond together, it appeared that the canopy protein was making mischief in the cell. Under normal conditions when only a few unfolded proteins showed up, the supervisor protein and the canopy protein were closely bonded together. But when too many unfolded proteins appeared, the supervisor protein left to activate the alert signals inside the cell, and the canopy protein was left alone. The canopy protein then began to activate more and more emergency signals, rather like running through the factory of the cell and pulling every alarm. Eventually, too many alarms caused liver cells to shut down, which caused livers to develop signs of fatty liver disease. 

These experiments showed that the canopy protein makes stress inside the cell worse when too many unfolded proteins appear. This study provides a solid link between how cells respond to unfolded proteins and how problems with metabolism can get out of hand in the liver and cause disease. Hong said this new understanding could help researchers develop treatments for non-alcoholic fatty liver disease and possibly other problems with metabolism. 

“This novel finding has raised the possibility of developing new treatments for metabolic diseases by targeting CNPY2,” said Hong. 

Li said this study also underscores the importance of basic research in medicine. "New CNPY2-targeted treatment won’t even be conceived without knowing what this molecule does in folding proteins and dealing with metabolic stresses."