Activin A is a Prominent Autocrine Regulator of Hepatocyte Growth Arrest

Activin A, a multifunctional cytokine, plays an important role in hepatocyte growth suppression and is involved in liver size control. The present study was aimed to determine the cell location of activin A in the normal rat liver microenvironment and the contribution of activin A signaling to the hepatocyte phenotype to obtain insight into molecular mechanisms. Immunohistochemical and hybridization analyses identified hepatocytes as the major activin A-positive cell population in normal liver and identified mast cells as an additional activin A source. To investigate paracrine and autocrine activin A-stimulated effects, hepatocytes were cocultured with engineered activin A-secreting cell lines (RF1, TL8) or transduced with an adeno-associated virus vector encoding activin βA, which led to strikingly altered expression of cell cycle-related genes (Ki-67, E2F transcription factor 1 [], minichromosome maintenance complex component 2 [], forkhead box M1 []) and senescence-related genes (cyclin-dependent kinase inhibitor 2B [p15/], differentiated embryo-chondrocyte expressed gene 1 []) and reduced proliferation and induction of senescence. Microarray analyses identified 453 differentially expressed genes, many of which were not yet recognized as activin A downstream targets (e.g., ADAM metallopeptidase domain 12 [], semaphorin 7A [], LIM and cysteine-rich domains-1 [], DAB2, clathrin adaptor protein []). Among the main activin A-mediated molecular/cellular functions are cellular growth/proliferation and movement, molecular transport, and metabolic processes containing highly down-regulated genes, such as cytochrome P450, subfamily 2, polypeptide 11 (), sulfotransferase family 1A, member 1 (), glycine-N-acyltransferase (), and bile acid-CoA:amino acid N-acyltransferase (). Moreover, Ingenuity Pathway Analyses identified particular gene networks regulated by hepatocyte nuclear factor (HNF)-4α and peroxisome proliferator-activated receptor gamma (PPARγ) as key targets of activin A signaling. : Our models demonstrated that activin A-stimulated growth inhibition and cellular senescence is mediated through p15/ and is associated with up- and down-regulation of numerous target genes involved in multiple biological processes performed by hepatocytes, suggesting that activin A fulfills a critical role in normal liver function. ( 2017;1:852-870).