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February 9, 2006

Liver protein that triggers inflammation may be linked to coronary artery disease, say U-M researchers

ANN ARBOR, MI – Scientists at the University of Michigan Medical School have identified a liver protein that triggers an inflammatory response in the liver and also may be involved in the development of coronary artery disease.

Press Release Image
Image shows CREBH (green), a liver-specific transcription factor, in the nucleus of liver cells where it activates inflammatory response genes. The nucleus is surrounded by endoplasmic reticulum (red). Photo credit: Kezhong Zhang, Ph.D., U-M Medical School.

The protein, called CREBH, is a transcription factor that turns on the activity of specific genes in liver cells. According to U-M scientists, CREBH is activated in response to cellular stress generated when unfolded proteins clog the endoplasmic reticulum – the part of a cell where new proteins are made.

“This is the first evidence indicating that an acute inflammatory response in the liver can be triggered by stress in the endoplasmic reticulum,” says Randal J. Kaufman, Ph.D., a Howard Hughes Medical Investigator and professor of biological chemistry in the U-M Medical School, who directed the research study.
 
Results of the study will be published in the Feb. 10 issue of Cell.

Scientists have known for some time that immune system cells release biochemical signals called cytokines, which travel through the bloodstream and activate an inflammatory response elsewhere in the body. But no one knew that liver inflammation could be triggered by signals from individual liver cells.

“Our study shows a direct connection between stress in the endoplasmic reticulum and the inflammatory response in the liver,” adds Kezhong Zhang, Ph.D., a U-M research investigator and the paper’s first author. “The link to heart disease is intriguing, because inflammation could be induced by several factors – infection, use of alcohol or a western-style diet – that cause ER stress and they are all potential risk factors for heart disease.”

U-M researchers discovered that CREBH regulates production of C-reactive protein (CRP), which is often found at elevated levels in the blood of heart attack patients and patients with autoimmune diseases. They also found evidence that CREBH is involved in production of apolipoprotein B (ApoB).  Both CRP and ApoB have been linked to a build-up of waxy fats and cholesterol in coronary arteries, which can lead to a heart attack.

“ApoB is the essential component of low-density lipoprotein, the so-called bad cholesterol,” Kaufman says. “There’s no question that high levels of LDL cholesterol are causative for heart disease. C-reactive protein in blood plasma is definitely a marker for inflammation, and recent evidence suggests it may be as important as cholesterol in assessing the risk of heart attack. It’s intriguing that regulation of cholesterol biosynthesis may be controlled by a biochemical pathway involving CREBH.”

To determine the function of CREBH protein, Kaufman and his colleagues on the U-M research team developed a strain of knock-down mice that were unable to produce normal amounts of the protein.  Without CREBH, the knock-down mice were unable to generate a strong inflammatory response, even to large amounts of substances known to trigger inflammation. Lacking the ability to produce CREBH, the mice had defects in activation of specific genes required to activate the inflammatory response in the liver.

Using a series of procedures, Zhang and other scientists discovered that the CREBH protein is split into two parts by proteases called S1P and S2P. One fragment of the CREBH protein travels to the nucleus to activate transcription of pro-inflammatory genes, including the genes for C-reactive protein and another protein called serum amyloid P-component (SAP). This entire biochemical pathway is triggered by stress in the endoplasmic reticulum.

“Our results suggest that many physiological and pathological processes that induce stress in the endoplasmic reticulum – such as mutations, cholesterol overload, infection or nutrient deprivation – can induce an inflammatory response through CREBH cleavage,” Kaufman says.

The study was funded by the Howard Hughes Medical Institute and the National Institutes of Health. The University of Michigan has filed a patent application on technology related to the CREBH pathway. The U-M's Office of Technology Transfer is actively seeking commercialization partners to help bring this technology to market.

Additional collaborators include: U-M research fellows Xiaohua Shen, Ph.D. and Kenjiro Sakaki, Ph.D.; Jun Wu, U-M graduate student; Thomas Saunders, Ph.D., research assistant professor; and D. Thomas Rutkowski and Sung Hoon Back, research associates in the Howard Hughes Medical Institute.

Citation: Cell: 124 (3), pp. 587-599, February 10, 2006 

Written by Sally Pobojewski

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