Selective inhibition of activated stellate cells and protection from carbon tetrachloride-induced liver injury in rats by a new PPARγ 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 γ (PPARγ) agonist, on the rate of cell proliferation and expression of α-smooth muscle actin (α-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 α-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 PPARγ proteins but decreased the cell cycle-related proteins, such as cdk2, cyclin B and cyclin D1. These changes were reversed by BADGE, a specific PPARγ antagonist, indicating that the effects of KR62776 are, at least in part, PPARγ-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.

Growth arrest and DNA damage-inducible 45α protects against nonalcoholic steatohepatitis induced by methionine- and choline-deficient diet

“…Additionally, more advanced fibrosis was seen in MCD-fed Gadd45a -null mice compared with the similarly-treated WT counterparts. These findings are consistent with a previous report that treatment with a peroxisome proliferator-activated receptor gamma agonist KR62776 suppresses stellate cell activation through Gadd45α induction and attenuates carbon tetrachloride-induced liver fibrosis in rats [25]. Additionally, a recent study revealed that knockdown of Gadd45α in isolated hepatic stellate cells enhanced carbon tetrachloride-induced ROS production [26].…”

The Active Components of Fuzheng Huayu Formula and Their Potential Mechanism of Action in Inhibiting the Hepatic Stellate Cells Viability – A Network Pharmacology and Transcriptomics Approach

“…Thus, increasing PPARG expression levels in HSCs should be an effective means of liver fibrosis prevention ( Galli et al, 2000 , 2002 ; Xu et al, 2003 ). Furthermore, some PPARG agonists, such as troglitazone, thiazolidinediones, saroglitazar, KR62776, GW7845, 6-octadecynoic acid, and 15d-PGJ2, have been proven to attenuate liver fibrosis by cell-based or animal experiments ( Marra et al, 2000 ; Galli et al, 2002 ; Zhao C. et al, 2006 ; Bae et al, 2010 ; Ohtera et al, 2013 ; Jain et al, 2017 ). PPARG agonists can therefore be concluded to be effective treatments for liver fibrosis by inhibiting the HSC activation; and PPARG is a promising therapeutic target for antifibrotic chemotherapy ( Zhang F. et al, 2013 ).…”

Fibronectin expression is critical for liver fibrogenesis in vivo and in vitro

“…In addition, activated HSCs are able to upregulate the expression of cytoskeletal proteins, including α-SMA. Therefore, α-SMA is considered a marker of HSC activation, which may reflect the degree of liver fibrosis ( 25 , 26 ). Alterations to the hepatic architecture occur due to the combined increase in cytoskeletal protein synthesis and the inability to break down these proteins, resulting in liver fibrosis and, eventually, cirrhosis ( 27 ).…”