S-Adenosylmethionine regulates connexins sub-types expressed by hepatocytes

Abstract

Intercellular communication via GAP Junctions plays an important role in tissue homeostasis, apoptosis, carcinogenesis, cell proliferation and differentiation. Hepatocyte connexins (Cx) 26 and 32 levels are decreased during the de-differentiation process of primary hepatocytes in culture, a situation that is also characterised by a decrease in S-Adenosylmethionine (SAMe) levels. In this current study, we show that SAMe supplementation in cultured hepatocytes every 12h, leads to an up-regulation of Cx26 and 32 mRNA and protein levels and blocks culture-induced Cx43 expression, although it failed to increase Cx 26 and 32 membrane localization and GAP junction intracellular communication. SAMe reduced nuclear β-catenin accumulation, which is known to stimulate the TCF/LEF-dependent gene transcription of Cx43. Moreover SAMe-induced reduction in Cx43 and β-catenin- was prevented by the proteasome inhibitor MG132, and was not mediated by GSK3 activity. SAMe, and its metabolite 5′-Methyltioadenosine (MTA) increased Cx26 mRNA in a process partially mediated by Adenosine A2A receptors but independent of PKA. Finally livers from MAT1A knockout mice, characterized by low hepatic SAMe levels, express higher Cx43 and lower Cx26 and 32 protein levels than control mice. These results suggest that SAMe maintains a characteristic expression pattern of the different Cxs in hepatocytes by differentially regulating their levels.

S-Adenosylmethionine and Methylthioadenosine Inhibit β-Catenin Signaling by Multiple Mechanisms in Liver and Colon Cancer

“…6C). This is consistent with Yamaji et al (2011), who observed that SAMe activated PP2A. Although the effect of SAMe may be via PP2A methylation, this is not the mechanism for MTA, as it was still effective even when its conversion to SAMe was blocked with cycloleucine.…”

“…5B). This is in agreement with Yamaji et al (2011); however, our results conflicted when we tested whether SAMe and MTA's inhibitory effect on b-catenin required GSK3b. Using the GSK3b-specific inhibitor TDZD-8, the ability of SAMe and MTA to lower b-catenin levels was abolished (Fig.…”

“…Using the GSK3b-specific inhibitor TDZD-8, the ability of SAMe and MTA to lower b-catenin levels was abolished (Fig. 5C), but Yamaji et al (2011), using either Kenpaullone or PHZ1123, found no influence. Differences in cell types may attribute the different effects exerted by SAMe.…”

“…1). One previous study showed a reduction of b-catenin levels in normal primary rat hepatocytes cultured for 24 hours with 4 mM SAMe; however, the mechanism was not fully elucidated (Yamaji et al, 2011). …”

Modifications in Connexin Expression in Liver Development and Cancer

“…Supplementation of the hepatocyte culture medium with this compound results in elevated Cx32 amounts and counteracts the appearance of Cx43. The latter is due to reduced accumulation of nuclear β -catenin, which in turn negatively affects Wnt signalling-dependent gene transcription of Cx43 (Yamaji et al, 2011).…”