The CCAAT/Enhancer-Binding Protein Beta - SerpinB3 Axis Inhibition as a Novel Strategy for Non-Alcoholic Steatohepatitis Treatment

SerpinB3: A Multifaceted Player in Health and Disease – Review and Future Perspectives

“…In a recent study 1-piperidine propionic acid (1-PPA) was able to inhibit PAR2, thus blocking a positive loop that involves the up-regulation of the early transcription factor CCAAT Enhancer Binding Protein beta (C/EBP-) and the subsequent promotion of SerpinB3 transcription [134]. In this study C/EBP- has been indeed reported as one of SerpinB3 transcription factors and plays a role in metabolic syndrome.…”

“…In particular, mice lacking the active form of SerpinB3 had at basal conditions not only lower levels of C/EBP- and a decreased fat mass, but also presented a lower inflammatory response after MCD or CDAA diet, whereas transgenic mice overexpressing SerpinB3 presented higher levels of C/EBP- than those of control mice, highlighting the essential role of the antiprotease activity of this serpin to achieve this effect. Notably, 1-PPA did not induce significant cell and organ toxicity, while inhibiting PAR2, C/EBP- and SerpinB3 synthesis in a dose-dependent manner at very low concentrations [134]. Notably, the precise mechanism of action of this compound has been identified, since it acts as an allosteric inhibitor of PAR2, showing the ability to stabilize the receptor in an inactive conformation, even at high temperatures [135] and therefore blocking the positive loop between SerpinB3-induced PAR2 and C/EBP-.…”