Drug & Device Development

IKK2 inhibition blocks liver steatosis in mice

Last Updated: 2008-06-03 15:36:57 -0400 (Reuters Health)

By David Douglas

NEW YORK (Reuters Health) - Pharmacological inhibition of the IKK2 activator of nuclear factor (NF)-kappa-B, using the agent AS602868, blocks steatosis and initiation of non-alcoholic liver steatohepatitis (NASH) in mice, according to European researchers.

"This is the second study where we found a benefit of the IKK2 inhibitor," senior investigator Dr. Christian Trautwein told Reuters Health. "Both studies demonstrate the inhibitor works in vivo in mice and therefore potential indications could be ischemia/reperfusion injury and NASH."

Dr. Trautwein of University Hospital, Aachen, Germany and colleagues, who note that IKK2 plays a key role in the development of NASH by mediating inflammation and insulin resistance, gave mice a high-sucrose diet along with daily doses of the IKK2 inhibitor.

This treatment prevented diet-induced weight gain and visceral fat accumulation. Treated mice also exhibited a lower degree of infiltrated macrophages along with reduced proinflammatory cytokine production.

"Further analysis," the researchers observe, "demonstrated that AS602868 treatment efficiently inhibited NF-kappa-B activation in liver non-parenchymal cells and as a consequence attenuated the inflammatory response in the liver."

In comments to Reuters Health, Dr. Fabio Marra of the University of Florence, author of an accompanying editorial, pointed out that the study "has the merit to focus our attention on inflammation in the liver and in the adipose tissue as a possible appealing target for the treatment of non-alcoholic steatohepatitis."

"Clearly," he concluded, "the efficacy and in particular the safety of NF-kappa-B inhibitors during long-term administration in humans need to be carefully assessed."

Gut 2008;57:655-663.