Science

Ribosomal S-6 kinase mediates development of liver fibrosis

Last Updated: 2008-01-08 15:41:52 -0400 (Reuters Health)

By Will Boggs, MD

NEW YORK (Reuters Health) - The ribosomal S-6 kinase (RSK)-C/EBP-beta phosphorylation pathway is critical for the development of liver fibrosis, according to a report in the December 26th PLoS.

"We are working in collaboration with other groups to develop small molecules active in this pathway," Dr. Martina Buck from University of California, San Diego, California told Reuters Health. "There is hope to cure hepatic fibrosis through the development of this and similar technologies."

Dr. Buck and Dr. Mario Chojkier used a mouse model of liver injury and fibrosis to investigate the role of RSK and phosphorylation of C/EBP-beta on Thr217 in hepatic stellate cells (HSC) in the development of liver fibrosis.

All mice with wild-type C/EBP-beta (having Thr217) developed severe liver fibrosis after exposure to carbon tetrachloride, the authors report, while mice with C/EBP-beta bearing Ala217 instead of Thr217 had minimal or no fibrosis.

Blocking phosphorylation of C/EBP-beta-Thr217 by inhibiting RSK activity also decreased the fibrotic response of the liver to chronic injury.

Mice expressing the RSK-inhibitory transgene (C/EBP-beta-Ala217) proved to be resistant to hepatotoxin-induced liver inflammation and HSC activation and proliferation.

Moreover, the investigators say, a C/EBP-beta-Ala217 peptide able to permeate cells stimulated cell death in hepatotoxin-induced activation of HSC and inhibited progression and stimulated regression of hepatotoxin-induced liver fibrosis.

Activated HSC in biopsies of human liver fibrosis showed increased expression of active RSK and C/EBP-beta Thr266 (the human equivalent of Thr217), the researchers note.

"This study suggests that blocking RSK activity inhibits fibrogenesis directly by inducing HSC apoptosis, and indirectly, by reducing liver injury and inflammation," the authors conclude. "We speculate that these findings may facilitate the development of small molecules potentially useful in the prevention and treatment of liver fibrosis."

PLoS 2007;2:e1372.