Changes in the expression of methionine adenosyltransferase genes and S-adenosylmethionine homeostasis during hepatic stellate cell activation.

UNLABELLED: Hepatic stellate cell (HSC) activation is an essential event during liver fibrogenesis. Methionine adenosyltransferase (MAT) catalyzes biosynthesis of S-adenosylmethionine (SAMe), the principle methyl donor. SAMe metabolism generates two methylation inhibitors, methylthioadenosine (MTA) and S-adenosylhomocysteine (SAH). Liver cell proliferation is associated with induction of two nonliver-specific MATs: MAT2A, which encodes the catalytic subunit alpha2, and MAT2beta, which encodes a regulatory subunit beta that modulates the activity of the MAT2A-encoded isoenzyme MATII. We reported that MAT2A and MAT2beta genes are required for liver cancer cell growth that is induced by the profibrogenic factor leptin. Also, MAT2beta regulates leptin signaling. The strong association of MAT genes with proliferation and leptin signaling in liver cells led us to examine the role of these genes during HSC activation. MAT2A and MAT2beta are induced in culture-activated primary rat HSCs and HSCs from 10-day bile duct ligated (BDL) rat livers. HSC activation led to a decline in intracellular SAMe and MTA levels, a drop in the SAMe/SAH ratio, and global DNA hypomethylation. The decrease in SAMe levels was associated with lower MATII activity during activation. MAT2A silencing in primary HSCs and MAT2A or MAT2beta silencing in the human stellate cell line LX-2 resulted in decreased collagen and alpha-smooth muscle actin (alpha-SMA) expression and cell growth and increased apoptosis. MAT2A knockdown decreased intracellular SAMe levels in LX-2 cells. Activation of extracellular signal-regulated kinase and phosphatidylinositol-3-kinase signaling in LX-2 cells required the expression of MAT2beta but not that of MAT2A.
CONCLUSION: MAT2A and MAT2beta genes are induced during HSC activation and are essential for this process. The SAMe level falls, resulting in global DNA hypomethylation.