1 HSC activation is associated with modulation of transcription factors such as the peroxisome proliferator-activated receptor (PPAR) class of nuclear receptors.2 PPARs regulate the expression of responsive genes by forming heterodimers
with retinoid X receptors. These SCH 900776 cell line heterodimers bind to DNA on a specific PPAR response element (PPRE), a hexameric direct repeat (called the DR1 element) separated by a single nucleotide (TGACCTnTGACCT).3 However, imperfect PPREs that are not exact matches of this hexameric repeat have also been identified in several genes with variations in the binding site and spacer sequence.4 Three subtypes of PPAR proteins are known, namely PPARα, PPARβ, and PPARγ, and all three are expressed by normal HSCs.5 PPARγ, an essential transcription factor involved in adipocyte differentiation, is highly expressed in quiescent or differentiated HSCs.6 However, its expression and activity decreases dramatically during HSC activation both in in vitro–cultured
HSCs and in in vivo–activated HSCs from livers of rats undergoing bile duct ligation (BDL).2 PPARγ expression can be restored in activated HSCs by treatment with specific ligands such as rosiglitazone (RSG) that are able to revert the activated phenotype to quiescent state with increased retinyl esters, increased expression of CCAAT/enhancer-binding FK506 in vitro proteins (C/EBP), decrease in collagen and α-SMA, and suppressed cell proliferation.6-8 In contrast to PPARγ, the PPARβ protein is strongly induced during HSC activation, and treatment of HSCs with PPARβ agonists induces cellular proliferation.3 Methionine adenosyltransferases (MATs) are critical for cell survival because they are responsible for the conversion of methionine to S-adenosylmethionine (SAM), an essential biological
methyl donor.9 Mammalian cells express two genes, MAT1A and MAT2A, that encode the two MAT catalytic subunits, α1 and α2, respectively. The α1 subunit organizes into dimers (MATIII) or tetramers (MATI).9, 10 The α2 subunit is found in the MATII isoform.11 A third gene, MAT2B, encodes for a β regulatory 4-Aminobutyrate aminotransferase subunit that regulates the activity of MATII by lowering the inhibition constant (Ki) for SAM and the Michaelis constant (Km) for methionine.12 MAT1A is expressed mainly in hepatocytes and maintains the differentiated state of these cells.12 MAT2A and MAT2B are expressed in extrahepatic tissues and are induced in liver during active growth and dedifferentiation.13, 14 In HSCs, SAM is synthesized only by MAT2A, because these cells do not express MAT1A.14 Recently, we demonstrated that both MAT2A and MAT2B genes are up-regulated during HSC activation.15 Interestingly, despite the increase in MAT2A, there was a rapid drop in the activity of the MATII enzyme and intracellular SAM levels during HSC activation.