What keeps hepatocytes on the straight and narrow? Maintaining differentiated function in the liver

Using conditioned medium from non-parenchymal cells from normal rat liver, Casteleijnet al demonstrated enhancement of hepatocyte glycogenolysis and modulation of the phosphorylation state of proteins secreted by hepatocytes, in each case attributed to prostaglandins. 6 7 Kupffer cell products from normal livers have also been reported to reduce protein synthesis and to depress cytochrome P-450 activity. 8 In inflammation, activation of Kupffer cells releases a variety of cytokines, leading to the well known modulation of hepatocyte protein synthesis that constitutes the acute phase response: upregulation of C-reactive protein, alpha-1-acid glycoprotein and fibrinogen production, and downregulation of-for example, albumin and transferrin. 9 Indeed, it is worth noting that the approach of isolating subpopulations to investigate normal liver function can be confounded by the artefactual induction of an acute phase response, if the preparative procedure itself leads to modulation of cytokine secretion by Kupffer cells. Conversely, transfection of the HNF4 gene into previously de-differentiated hepatoma cells which do not express HNF4 cells causes an increase in differentiated function. 29 At a more clinical level there is a case report of an individual with severe factor VII deficiency whose phenotype seems to be due to a single nucleotide transposition in the gene promoter in the region that should bind HNF4, leading to a 93% decrease in promoter activity in vitro. 30 Transcription factor activity is, however, very complex, and there is evidence of cross regulation of gene expression by different members of the HNF family on one another-for example, HNF1 and HNF4 regulate the action of one another's promoter, and HNF6 regulates the transcription of liver specific genes partly by its action on the HNF3 gene. 27 As would be anticipated, a change from a non-proliferating to a proliferating state, induced by hepatic resection for example, is associated with striking changes in LETF activity modulating changes in gene expression. 31 CEBP-β has also been implicated in the control of the acute phase response and more recently there is evidence that it plays a role in cell cycle control. 32 Summary The conventional physiological requirements of fluid flow, oxygenation, nutrition, and removal of waste products are only the tip of the iceberg of the requirements for maintaining differentiated hepatocyte function in vivo or replicating it in vitro.