Selective inhibition of activated stellate cells and protection from carbon tetrachloride-induced liver injury in rats by a new PPARgamma agonist KR62776.

Abstract

Activated hepatic stellate cells (HSC) are the primary source of extracellular matrix proteins found in liver fibrosis/cirrhosis patients. Therefore, the prevention of HSC activation is an important strategy for treating severe liver injury. This study examined the effects of KR62776, a new peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, on the rate of cell proliferation and expression of alpha-smooth muscle actin (alpha-SMA) in rat hepatic stellate HSC-T6 cells. In addition, its effects on the liver damage induced by carbon tetrachloride were investigated. KR62776 caused the apoptosis of activated HSC-T6 cells with the concomitant decrease in the alpha-smooth muscle actin levels in a time- and concentration-dependent manner. However, KR62776 did not cause the apoptosis of human HepG2 and rat McARH7777 hepatoma cells, suggesting that KR62776 has a specific effect on stellate cells. KR62776 increased the levels of Gadd45, p27, p21 and PPARgamma proteins but decreased the cell cyclerelated proteins, such as cdk2, cyclin B and cyclin D1. These changes were reversed by BADGE, a specific PPARgamma antagonist, indicating that the effects of KR62776 are, at least in part, PPARgamma-dependent. In addition, KR62776 administration showed some protection against carbon tetrachloride-induced hepatocellular damage in rats. Overall, these results suggest that KR62776 may have potential in the chemoprevention of liver fibrosis/cirrhosis.

• Authors: Myung-Ae Bae, Sang Dal Rhee, Won Hoon Jung, Jin Hee Ahn, Byoung-Joon Song, Hyae Gyeong Cheon
• Journal: Archives of pharmacal research (Arch Pharm Res) Vol. 33 Issue 3 Pg. 433-42 (Mar 2010) ISSN: 1976-3786 [Electronic] Korea (South)
• PMID: 20361309 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Cell Cycle Proteins
• Indans
• KR 62776
• Oximes
• PPAR gamma
• Protective Agents
• RNA, Messenger
• smooth muscle actin, rat
• Carbon Tetrachloride

Topics

• Actins (metabolism)
• Animals
• Apoptosis (drug effects)
• Carbon Tetrachloride
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Proliferation (drug effects)
• Chemical and Drug Induced Liver Injury (etiology, metabolism, pathology, prevention & control)
• Cytoprotection
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression Regulation (drug effects)
• Hep G2 Cells
• Hepatic Stellate Cells (drug effects, metabolism, pathology)
• Humans
• Indans (pharmacology)
• Liver (drug effects, metabolism, pathology)
• Liver Cirrhosis (chemically induced, metabolism, pathology, prevention & control)
• Male
• Oximes (pharmacology)
• PPAR gamma (agonists, genetics, metabolism)
• Protective Agents (pharmacology)
• RNA, Messenger (metabolism)
• Rats
• Rats, Wistar
• Time Factors