Then, they showed that this suppression of hepatocyte proliferati

Then, they showed that this suppression of hepatocyte proliferation by activated HSCs selleck kinase inhibitor occurs through serotonin signaling, which promotes the production of transforming growth factor-β1 (TGF-β1), a potent mediator of hepatocyte proliferation and fibrogenesis (Fig. 1). Serotonin (5-hydroxytryptamine [5-HT]) is a neurotransmitter that is also involved in tissue remodeling.5 Platelets serve as the major source of serotonin (∼95%) in the blood.6 In the liver, platelet-derived serotonin regulates liver regeneration by binding to 3 isoforms of 5-HT2 receptors, 5-HT2A, 5-HT2B, and 5-HT2C.7 Among these serotonin receptors, the 5-HT2B receptor was previously reported

to be expressed on activated HSCs in diseased livers.8 The authors examined a role for the 5-HT2B receptor for hepatocyte proliferation in liver injury and found that its inhibition increased hepatocyte proliferation. In contrast, a specific inhibitor of the other 2 isoform receptors, 5-HT2A

and 5-HT2C, did not influence hepatocyte proliferation, indicating that 5-HT2B receptors on activated HSCs selectively block hepatocyte proliferation in their BMN 673 research buy study. In addition to their role in diseased livers, 5-HT2B receptors on HSCs also play an inhibitory role in hepatocyte proliferation in the regenerative response of normal livers after partial hepatectomy (PHx). Mice lacking 5-HT2B receptors and normal mice treated with a specific 5-HT2B receptor antagonist (SB-204741) demonstrated increased hepatocyte proliferation in response to PHx. These mice also showed decreased expression of medchemexpress TGF-β1 in the regenerating liver, suggesting that TGF-β1 plays a critical role in the 5-HT2B receptor-mediated inhibition of hepatocyte proliferation. However, in spite of the dramatic reduction in TGF-β1 expression, differences in the liver-to-body-weight

ratio between mice treated with the 5-HT2B receptor antagonist and controls were small. This modest result in the PHx model contrasts with the far more robust hepatocyte proliferation seen in 2 injury models where 5-bromo-2′-deoxyuridine and proliferating cell nuclear antigen labeling were 2- to 5-fold greater in mice treated with the 5-HT2B receptor antagonist. These findings indicate that the 5-HT2B receptor-mediated regenerative response is one of many overlapping pathways involved in reconstituting normal livers, whereas its role in hepatocyte proliferation in the diseased liver may be more critical. Additional evidence to support the complexity of serotonin and 5-HT receptor interactions is the observation that serotonin can either positively or negatively regulate hepatocyte proliferation, depending on the receptors to which it binds. In contrast to the findings of the current study, several studies7, 9 have shown that platelet-derived serotonin promotes hepatocyte proliferation. In vitro, for example, serotonin is a mitogen that promotes hepatocyte proliferation. Additions of serotonin to cell culture media increase DNA synthesis in primary rat hepatocytes.

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