Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo

Abstract

Background: Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic “gain-of- function” inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD- mediated liver disease. Methods: EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples. Results: We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs.Conclusion: AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease.

Liver disease with unknown etiology – have you ruled out alpha-1 antitrypsin deficiency?

“…Whether this occurs in situ is yet to be determined. 13 AATD is one of the three most frequently occurring genetic liver disorders, along with Wilson's disease and hemochromatosis. 14 Although there are many genotypes associated with AATD, liver disease is more strongly associated with the PI*ZZ and PI*SZ genotypes, and has some association with the PI*MZ genotype.…”