Alpha-1 antitrypsin (AAT) deficiency is a genetic disease that can affect both the lung and the liver. The vast majority of patients harbor a mutation in the SERPINA1 gene resulting in a single substitution from glutamic acid to lysine at amino acid position 342 (p.E342K). The AAT encoded by the Z allele (ATZ) is not properly folded and accumulates in the endoplasmic reticulum (ER) of hepatocytes resulting in liver disease through a gain of function mechanism. The liver disease is a prototype of conformational disorder due to protein misfolding and aggregation. Intracellular retention of ATZ triggers a complex injury cascade including autophagy, ER-stress and other mechanisms. Nevertheless, several aspects of the disease pathogenesis are still unclear. I found that ATZ induces activation of c-JUN N-terminal kinase (JNK) and c-JUN signaling in livers of a mouse model (PiZ mice) of the disease. JNK activation was confirmed in human livers of patients homozygous for the Z allele with severe liver disease requiring hepatic transplantation. In mice, genetic ablation of Jnk1 or Jnk2 decreased ATZ levels by reducing c-JUN mediated SERPINA1 expression. Moreover, I have found up-regulation of genes associated with response to ER stress in PiZ mouse livers by expression array profiling. Among the differentially expressed genes, I focused on the CCAAT/Enhancer-Binding Protein Homologous Protein (Chop) that was significantly up-regulated in both mouse and human livers expressing ATZ. To investigate the role of CHOP in ATZ-induced liver damage, I crossed PiZ with Chop null (Chop-/-) mice. Genetic ablation of Chop resulted in a marked reduction of hepatic ATZ levels in juvenile PiZ mice. SERPINA1 mRNA levels in livers of PiZ/Chop-/- mice were also significantly reduced compared to PiZ controls, suggesting that CHOP induces ATZ accumulation by increasing SERPINA1 transcription. CHOP was indeed found to up-regulate SERPINA1 expression through binding with C/EBPβ and c-JUN on SERPINA1 regulatory elements. So far, JNK and CHOP have been involved in the pathogenesis of several liver disorders but not in hepatic disease induced by ATZ. The results of my studies show that JNK and CHOP are important players in the disease pathogenesis and are novel therapeutic targets.
ROLE OF JNK AND CHOP IN THE PATHOGENESIS OF LIVER DISEASE DUE TO Z ALPHA-1 ANTITRYPSIN / S. Attanasio ; internal advisor: C. Settembre ; external advisor: M. E. Banos Miranda. - Milano : Università degli studi di Milano. Universita' degli Studi di MILANO, 2019 Jan 28. ((30. ciclo, Anno Accademico 2018.
|Titolo:||ROLE OF JNK AND CHOP IN THE PATHOGENESIS OF LIVER DISEASE DUE TO Z ALPHA-1 ANTITRYPSIN|
|Tutor esterno:||BRUNETTI PIERRI, NICOLA|
|Data di pubblicazione:||28-gen-2019|
|Parole Chiave:||Alpha-1 antitrypsin deficiency; CHOP; JNK;|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Citazione:||ROLE OF JNK AND CHOP IN THE PATHOGENESIS OF LIVER DISEASE DUE TO Z ALPHA-1 ANTITRYPSIN / S. Attanasio ; internal advisor: C. Settembre ; external advisor: M. E. Banos Miranda. - Milano : Università degli studi di Milano. Universita' degli Studi di MILANO, 2019 Jan 28. ((30. ciclo, Anno Accademico 2018.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/attanasio-sergio_phd2019-01-28|
|Appare nelle tipologie:||Tesi di dottorato|