Platelet-Derived Serotonin Mediates Liver Regeneration

Abstract

The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration.

Gene Expression Profiling Provides Insights into Pathways of Oxaliplatin-Related Sinusoidal Obstruction Syndrome in Humans

“…The role of clotting abnormalities in the experimental SOS model (34) and in humans is matter of debate. Injury to SEC creates a procoagulant condition in the sinusoids and overexpression of MMPs could be associated with increased platelet adhesion as is observed following cold preservation of liver (35). However, ultrastructural studies of livers from individuals with bush tea-related SOS revealed no evidence of clotting abnormalities (36) and immunohistochemical studies of autopsy livers did not detect platelets, although fibrinogen and factor VIII were detected in the hepatic veins (37).…”

“…Conversely, thrombocytopenia has recently been shown as being associated with severe oxaliplatin-related SOS in humans (38). Because of the role of platelets in liver regeneration through a serotoninmediated mechanism (35), alteration in platelet function could play a role in postoperative liver insufficiency that may occur following severe SOS lesions. Our results underline the role of coagulation in SOS and open the possibility of therapeutic approaches to prevention oxaliplatin-associated liver injury, such as aspirin that has been associated with reduced risk for sinusoidal lesions (13).…”

Cellular and molecular mechanisms in liver fibrogenesis

“…By using the conventional procedure of 70% partial hepatectomy (PHX) as a model to induce liver regeneration it has been described that, following surgical intervention, serotonin is rapidly mobilized from gut and accumulates in the remnant liver, possibly delivered here by platelets [148], although the latter hypothesis has been recently challenged. Available data suggest in any case that 5-HT can sustain hepatocyte proliferation following PHX, likely by acting through a restrict number of receptors (5-HT1A, 2A and 2B), as also unequivocally indicated by the significant impairment of regeneration observed in Tph−/− mice [147,148]. Recently, it has proposed that cholangiocytes may represent an additional source of serotonin as resident liver cells, with serotonin that once released can in turn represses cholangiocyte proliferation through a negative feedback mechanism [149].…”

Stimulation of glycogen synthesis and inactivation of phosphorylase in hepatocytes by serotonergic mechanisms, and counter-regulation by atypical antipsychotic drugs

“…High concentrations of 5-HT occur in vivo during tissue injury, when platelet aggregation results in the release of stored 5-HT. This mechanism is involved in liver regeneration after partial hepatectomy [5]. Since glycogenesis is suppressed during liver regeneration [34], high concentrations of 5-HT may have a dual role in suppressing glycogenesis and stimulating hepatocyte proliferation [5,34].…”

“…In addition to its role as a neurotransmitter, 5-HT has a range of functions that include control of vascular tone, exocrine secretion by the pancreas [4], liver regeneration [5] and glucose homeostasis [6][7][8]. Studies in vivo have shown either hypoglycaemia [6,7] or hyperglycaemia [8] after administration of 5-HT.…”