Study confirms protein culprit in alcohol-induced liv...( ed levels of endotoxin intocirculation...)

ed levels of endotoxin into circulation. This, in turn, may activate Kupffer cells to release many potent cytokines, including TNF-alpha. The resultant output could lead to liver injury. The UNC study was led by Dr. Ming Yin, a research associate in Thurman's Laboratory of Hepatobiology and Toxicology. The researchers studied mice lacking receptor sites for TNF-alpha on their liver cell surfaces. These "knocked-out" receptors were TNF-R1 and TNF-R2.

Yin and his colleagues successfully adapted a feeding system to this mouse model that would allow a continuous infusion of a high-fat diet with alcohol directly into the stomach via a tube, without curtailing the animals' mobility. "The use of animals lacking TNF receptors provides a direct way to test the hypothesis that this cytokine is important in initiation and progression of alcohol-induced liver injury," the researchers state.

Compared to "wild-type" mice and those lacking TNF-R2 , the TNF-R1 knockouts fared significantly better on measures of liver injury after four weeks of continuous alcohol (ethanol) exposure. These included measures of liver enzymes, steatosis (fatty liver), and liver pathology.

"Ethanol caused severe liver injury in wild-type mice and TNF-R2 knockout mice but not in TNF-R1 knockout mice," the report states. "Moreover, the long-term enteral ethanol feeding technique we described for the first time for knockout mice provides a useful new tool for alcohol research."

Says Thurman: "The next step will be to try out our knockout technology for [liver] fibrosis. We would use the same model, just go longer with it." He adds: "Alcoholic liver disease is more common in men than women but the most sensitive group are overweight females. So we're hypothesizing that estrogen plays a role in the mechanism of pathology." In that regard, Thurman plans to apply the study's technology to estrogen receptor knockout mice.

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Contact: Lynn Wooten
Lwooten@unch.unc.edu
919-966-6046
University of North Carolina School of Medicine
1-Oct-1999

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