Abstract
Reversal of activated hepatic stellate cells (HSCs) to a quiescent state and apoptosis of activated HSCs are key elements in the reversion of hepatic fibrosis. CCAAT/enhancer binding protein α (C/EBP-α) has been shown to inhibit HSC activation and promote its apoptosis. This study aims to investigate how C/EBP-α acetylation affects the fate of activated HSCs. Effects of a histone deacetylation inhibitor trichostatin A (TSA) on HSC activation were evaluated in a mouse model of liver fibrosis caused by carbon tetrachloride (CCl4) intoxication. TSA was found to ameliorate CCl4-induced hepatic fibrosis and improve liver function through increasing the protein level and enhancing C/EBP-α acetylation in the mouse liver. C/EBP-α acetylation was determined in HSC lines in the presence or absence of TSA, and the lysine residue K276 was identified as a main acetylation site in C/EBP-α protein. C/EBP-α acetylation increased its stability and protein level, and inhibited HSC activation. The present study demonstrated that C/EBP-α acetylation increases the protein level by inhibiting its ubiquitination-mediated degradation, and may be involved in the fate of activated HSCs. Use of TSA may confer an option in minimizing hepatic fibrosis by suppressing HSC activation, a key process in the initiation and progression of hepatic fibrosis.
Highlights
Growing clinical evidence has demonstrated that hepatic fibrosis and early cirrhosis may be reversible with effective etiology eradication[1,2] and that the reversal of activated hepatic stellate cells (HSCs) to a quiescent state and their apoptosis are key elements to the reversion of hepatic fibrosis[3,4]
Immunohistochemical staining for collagen type I demonstrated that deposition of extracellular matrix (ECM) components was significantly reduced in the CCl4 plus trichostatin A (TSA)-concurrent group and CCl4 plus TSA-late group (2.45 ± 0.4 and 3.1 ± 0.43%, respectively) compared to CCl4 or CCl4 plus DMSO groups (6.56 ± 0.47 and 6.56 ± 0.83%, respectively)
HSC activation plays a pivotal role in the advance of liver fibrosis, and these cells represent an appealing target for anti-fibrotic therapy
Summary
Growing clinical evidence has demonstrated that hepatic fibrosis and early cirrhosis may be reversible with effective etiology eradication[1,2] and that the reversal of activated hepatic stellate cells (HSCs) to a quiescent state and their apoptosis are key elements to the reversion of hepatic fibrosis[3,4]. Methylation, phosphorylation and ubiquitination of C/EBP-α are involved in a number of physiological processes and may be involved in many diseases[9,10,11,12]; the physiological role of C/EBP-α acetylation has been poorly understood in HSCs, which play a critical role as an effector in hepatic fibrosis. The present study aims to determine how the fate of activated HSCs is affected by C/EBP-α acetylation in HSC lines and an animal model of hepatic fibrosis. HSC lines and primary rat HSCs were used to dissect how C/EBP-α acetylation affected the fate of activated HSCs. Our findings suggest that deacetylation inhibitors, such as TSA, could be potential approach in suppressing hepatic fibrosis
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