Activin B promotes the initiation and progression of liver fibrosis

Joint Event: 15^th European Pharma & Biosimilars Congress and 20^th International Conference and Exhibition on Materials Science and Chemistry

April 25-26, 2022 Barcelona, Spain

Guoli Dai

Indiana University-Purdue University Indianapolis, USA

Keynote: Pharm Regul Aff

Abstract :

Background & Aims: Liver fibrosis is a pivotal pathology in multiple hepatic disease indications, profoundly characterizing disease severity and outcomes. The role of activin B, a TGFβ superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Methods: Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl4)-induced liver fibrosis. The direct effects of activin B and A on hepatocytes and hepatic stellate cells (HSCs) were evaluated in vitro. Results: As a result, hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. We found that neutralizing activin B largely prevented, as well as remarkably regressed, CCl4-induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B directly promotes hepatocyte death, induces a profibrotic expression profile in HSCs, and stimulates HSCs to form a septa structure. In addition, activin B and A interdependently upregulated the transcription of profibrotic factors including connective tissue growth factor and TGFβ1 in injured livers. Conclusions: We demonstrate that activin B, cooperating with activin A, directly acts on multiple liver cell populations, and drives the initiation and progression of liver fibrosis. Our finding inspires the development of a novel therapy of chronic liver diseases.

Biography :

Dr. Guoli Dai is an associate professor in the Department of Biology, School of Science, Center for Developmental and Regenerative Biology, in Indiana University-Purdue University Indianapolis (IUPUI). His research interest focuses on molecular and cellular mechanisms controlling liver growth and regeneration.