Researchers unravel liver dysfunction, infection link

By Ruth SoRelle, M.P.H.

For more than 100 years, physicians have recognized that the livers of patients with serious infections do not work well. The livers of infants with infections are particularly affected.

Why that happens remained a mystery, but a recent study by Saul Karpen, M.D., Ph.D., and colleagues at Baylor College of Medicine in Houston may have begun to unravel the puzzle.

"The thing that intrigued me as a pediatric liver doctor is that babies are more susceptible to the effects of inflammation on their livers than older people," said Karpen. "The first presentation (or sign) of an illness in an infant might be jaundice – not fever or just looking ill." (Jaundice is a yellowing of the skin and the whites of the eyes.) Karpen is an associate professor of pediatrics in the division of pediatric gastroenterology at BCM and director of the Texas Children's Liver Center.

Impact on master gene

The answer may lie in how infection – and particularly the inflammation associated with it – affects the activity of a master gene known as retinoid X receptor alpha (RXR alpha).

Karpen and his colleagues believe that a cascade of cellular activity set off by the inflammation reduces the activity of RXR alpha, a receptor in the nucleus that acts as a master controller of a broad class of genes critical to proper functioning of liver cells.

Previously, when Karpen and his colleagues studied models of inflammation and infection in the laboratory, they found less RXR alpha in the nuclei of cells affected by these factors. This indicated that the activity of RXR alpha was suppressed in the presence of infection and inflammation.

"If there is less of this regulator protein in the nucleus, then the ability of the liver to express genes regulated by RXR alpha has to be lower," said Karpen.

In a recent study in the Journal of Biological Chemistry, Karpen and his BCM collaborators tested the premise in the laboratory, using cells grown in culture. To do this, they used a cytokine. A cytokine is a small protein involved in the immune process. In some disease, the expression of cytokines is abnormal.

In this case, the researchers treated cells with a cytokine called interleukin-1 beta (Il-1 beta) that is expressed at high levels in many inflammatory conditions.

Implications of finding

They found that within 30 minutes of treating cells with the cytokine, the RXR alpha gene is transported out of the nucleus. Key to this action is a particular point on RXR alpha called serine 260. If serine 260 is mutated, the RXR remains in the nucleus and can fulfill its function.

The finding has implications for understanding liver disease and the effectiveness of treatments developed for it.

"This finding about inflammation and inflammatory cascades interacting with important gene regulators like RXR alpha within the liver cell nucleus may demonstrate why treatments are not always able to function as effectively as we anticipate," said Karpen. It also raises the possibility that new drugs to fight inflammation or keep nuclear receptors in the nucleus could be developed.

"One anticipates that this is a situation amenable to drug therapy," said Karpen. However, he said, that therapy has yet to be developed, and doing so will take time and further studies.

Others who participated in this work include Tracy L. Zimmerman and Drs. Sundararajah Thevananther, Romi Ghose and Alan R. Burns, all of BCM and the Texas Children's Liver Center.

This research was supported by the National Institutes of Health, the Texas Gulf Coast Digest Diseases Center and the Texas Children's Hospital Foundation.