Regulation of liver metabolism by intercellular communication.

The regulation of liver metabolism by intercellular communication was assessed by studying the effect of conditioned media of Kupffer and liver endothelial cells on protein synthesis, protein phosphorylation and glycogenolysis in parenchymal cells. Kupffer and endothelial cell-conditioned media enhanced the rate of protein synthesis of parenchymal cells by a factor of 1.7-1.9. The phosphorylation state of only three specific parenchymal cell proteins was influenced by the conditioned media. One, the MW 97,000 band appeared to be phosphorylase and it was found that in parallel with an enhancement of the activity of phosphorylase the glucose output by parenchymal cells could be stimulated. The effects of the conditioned media could be mimicked by prostaglandin E1, E2 and D2, whereas the pretreatment of non-parenchymal cells with aspirin abolished the stimulatory effect of these cells on the glucose output by parenchymal cells. The data indicate that prostaglandins from Kupffer and endothelial cells, mainly PGD2, can influence glucose release from parenchymal cells. The physiological importance of cellular communication was further assessed in a liver perfusion system. The tumor promoting phorbol ester PMA stimulated glycogenolysis in the perfused liver two-fold. This stimulation was blocked by the presence of aspirin. PMA is inactive on isolated parenchymal cells. Addition of PMA to the perfused liver appears to enhance the output of PGD2 in parallel with the stimulation of the glucose output. Addition of prostaglandin D2 itself could also stimulate the glucose output in the perfused liver. Our data indicate that the stimulation of glycogenolysis in the liver by PMA is mediated by non-parenchymal cells which produce PGD2 in response to PMA, leading subsequently to activation of the phosphorylase system in the parenchymal cells. It seems possible also that the tumor-promoting activity of PMA on liver will be mediated by a primary interaction with non-parenchymal cells. It is concluded that the occurrence of intercellular communication inside the liver in response to activation of non-parenchymal cells adds a new mechanism to the complex regulation of liver metabolism which may be relevant under normal and pathological conditions.