Glucocorticoid Regulation of HepaticS-Adenosylmethionine Synthetase Gene Expression¹

Abstract

The effects of glucocorticoids on the regulation of rat liver S-adenosylmethionine synthetase were studied in vivo and in two culture systems. Livers from adrenalectomized animals were examined for enzyme activity, immunoreactive protein, and messenger RNA (mRNA) content. All three parameters showed a similar trend, i.e. they decreased 3-fold after adrenalectomy and increased over the control values upon triamcinolone replacement. These results suggested that glucocorticoid regulation of hepatic S-adenosylmethionine synthetase was mediated at the mRNA level. Triamcinolone and dexamethasone increased S-adenosylmethionine synthetase mRNA content in a time- and dose-dependent manner in both rat hepatoma H35 cells and primary cultures of adult rat hepatocytes. The kinetics of mRNA induction were identical in both culture systems, indicating that the hormone-mediated response is independent of the differentiated state of the cell. Insulin blocked the inducing effect of glucocorticoids on S-adenosylmethionine synthetase mRNA in a dose-dependent manner. On the other hand, the triamcinolone-dependent increase in mRNA levels was completely abolished by treatment with actinomycin D, whereas cycloheximide did not affect this response. The transcription rate of the gene, as measured by run-on assay, increased 3-fold after hormone addition. Transient transfections of H35 cells with 1.4 kilobases of the 5'-flanking region of the hepatic S-adenosylmethionine synthetase gene fused to a luciferase reporter gene showed that promoter activity is also increased 3-fold after triamcinolone treatment, suggesting that this promoter region contains the sequence elements necessary to confer glucocorticoid responsiveness. In addition to the transcriptional control of the hepatic S-adenosylmethionine synthetase gene, our results suggest that glucocorticoids may be acting at a posttranscriptional level.

Modulation of Methyl Group Metabolism by Streptozotocin-induced Diabetes and All-trans-retinoic Acid

“…In support of the increase in CBS abundance that we reported, we also found that the hepatic concentration of AdoMet was elevated in agreement with previous studies using hyperglucogonemic rats (20). Elevations in hepatic AdoMet levels may be the result of increased expression of methionine adenosyltransferase, as it is up-regulated by glucocorticoids (34). An increase in hepatic AdoMet concentrations would also be expected to reduce 5-CH 3 -THF levels as a result of allosteric inhibition of 5,10-methylenetetrahydrofolate reductase (9,10).…”

Characterization of Rat Liver-specific Methionine Adenosyltransferase Gene Promoter

“…The finding that element B negatively regulates MAT transcription is in agreement with this hypothesis, since HNF1 is a positive regulatory factor (50,51), and vHNF-1 has been shown to be involved in the negative regulation of some liver-specific genes (55). In this context, it should be mentioned that steady-state levels of liver-specific MAT mRNA are lower in rat hepatoma H35 cells than in hepatocytes (15). A similar pattern of reduced expression has been also detected for the human hepatic mRNA in the hepatoma HepG2 cell line, 2 a finding that does not completely agree with a previous report suggesting a complete lack of transcription of the liver MAT gene in these cells (13).…”

“…In contrast, a marked reduction of MAT gene expression has been reported in human hepatocarcinoma (13) and in a rat model of hypoxiainduced liver injury (14). On the other hand, glucocorticoids (15) and cAMP (8) increase the expression of the gene in rats, whereas insulin blocks the inducing effect of glucocorticoids (8). Altogether, these results suggest that hepatic MAT gene expression is regulated differently under various normal and pathophysiological conditions.…”

Pattern of methionine adenosyltransferase isoenzyme expression during rat liver regeneration after partial hepatectomy

“…Concerning the mechanisms that may operate to induce MAT isoenzyme switch during liver regeneration, it has been reported that the balance between cell proliferation and differentiation is strictly regulated in a time‐dependent process by a pool of cytokines, growth factors and hormones [1, 27]. In this context, it is worth noting that MAT I/III expression is modulated by several of these extracelluar factors [14, 28–30], and within the promoter of the liver‐specific gene there are cytokine‐responsive elements [31].…”