Increased expression of pregnancy-associated plasma protein-A (PAPP-A) in hepatic stellate cells correlates with hepatic fibrosis and can be detected in the serum of patients with liver disease

Pregnancy-associated plasma protein-A (PAPP-A) was firstly discovered as a placental protein present in the circulation of pregnant women. PAPP-A is a metalloproteinase that specifically cleaves insulin-like growth factor (IGF) binding proteins (IGFBPs). It binds tightly to glycosaminoglycans present on the cell surface and thus functions as a growth-promoting enzyme, releasing bioactive IGF in close proximity to the IGF receptor. Recently, we have discovered PAPP-A as a tumor promotor in hepatocellular carcinoma applying causal modeling (PLoS Comput Biol. 2015;11(5):e1004293). Although the IGF-system is known to play a critical role in liver fibrosis, no further information existed regarding the expression and function of PAPP-A in chronic liver disease.

Therefore, the aim of this study was to analyze the expression and function of PAPPA in liver fibrosis.

Methods and Results: Hepatic PAPP-A expression was significantly increased in different murine models of hepatic fibrosis (toxic liver injury with TAA or CCl4, bile duct ligation and dietary models of non-alcoholic fatty liver disease). Furthermore, PAPPA expression revealed a significant correlation with collagen I and alpha-smooth-muscle expression in human hepatic tissue specimens from patients with chronic liver disease. Moreover, PAPPA serum levels were significantly increased in patients with cirrhosis as compared to individuals without liver disease. Fitting to this, PAPPA expression significantly increased in hepatic stellate cells (HSC) during in vitro activation, and suppression of PAPPA expression in activated HSC with siRNA resulted in reduced PAPPA secretion into the supernatant. Furthermore, PAPPA suppressed HSCs showed significantly reduced proliferation as compared to HSC transfected with control siRNA. In addition to PAPP-A, we newly discovered strong expression of IGFBP-4 in activated human HSCs, and analysis of human activated HSC isolated from 14 different donors revealed a significant correlation between PAPP-A and IGFBP-4 expression.

Summary and Conclusion: PAPP-A expression and secretion increase during activation of HSC, and our data suggest that this leads to an autocrine induction of HSC proliferation, potentially via cleavage of IGFBP-4 and consecutive release of (bioactive) IGF. This indicates PAPP-A as novel target for anti-fibrogenic therapy. Moreover, activated HSC appear to be the major source of PAPP-A in diseased livers, and herewith, circulating PAPP-A levels appear as potential novel biomarker for hepatic fibrosis.