Alpha‐1‐antitrypsin deficiency: from genoma to liver disease. PiZ mouse as model for the development of liver pathology in human

Giovannoni, Isabella; Callea, Francesco; Stefanelli, Marta; Mariani, Rosanna; Santorelli, Filippo M.; Francalanci, Paola

doi:10.1111/liv.12504

Cited by 18 publications

(19 citation statements)

References 29 publications

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“…Therefore, hepatocyte dedifferentiation by down‐regulation of HNF‐4α appears to occur early in response to ATZ‐mediated damage in PiZ livers. In agreement with these data, preneoplastic lesions and HCC in PiZ mice have been found to express immature hepatic marker α‐fetoprotein, but they were lacking expression of genes expressed in mature hepatocyte genes, such as glucose‐6‐phospatase …”

Section: Discussionsupporting

confidence: 75%

“…In agreement with these data, preneoplastic lesions and HCC in PiZ mice have been found to express immature hepatic marker a-fetoprotein, but they were lacking expression of genes expressed in mature hepatocyte genes, such as glucose-6-phospatase. (36) HNF-4a controls SERPINA1 expression, (22) and thus, its reduced expression might serve as a defensive mechanism activated to reduce the burden of toxic ATZ. We indeed observed age-dependent reductions of SERPINA1 expression and PAS-D-positive globules in PiZ mouse livers that were paralleled by a greater reduction of Hnf4a expression in older compared to younger PiZ mice.…”

Section: Discussionmentioning

confidence: 99%

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Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin

et al. 2017

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a 1 -Antitrypsin (AAT) deficiency is one of the most common genetic disorders and the liver disease due to the Z mutant of AAT (ATZ) is a prototype of conformational disorder due to protein misfolding with consequent aberrant intermolecular protein aggregation. In the present study, we found that livers of PiZ transgenic mice expressing human ATZ have altered expression of a network of hepatocyte transcriptional factors, including hepatocyte nuclear factor-4a, that is early down-regulated and induces a transcriptional repression of ATZ expression. Reduced hepatocyte nuclear factor-4a was associated with activation of b-catenin, which regulates liver zonation. Livers of PiZ mice and human patients with AAT deficiency were both found to have a severe perturbation of liver zonation. Functionally, PiZ mice showed a severe defect of ureagenesis, as shown by increased baseline ammonia, and reduced urea production and survival after an ammonia challenge. Down-regulation of hepatocyte nuclear factor-4a expression and defective zonation in livers have not been recognized so far as features of the liver disease caused by ATZ and are likely involved in metabolic disturbances and in the increased risk of hepatocellular carcinoma in patients with AAT deficiency. Conclusion: The findings of this study are consistent with the concept that abnormal AAT protein conformation and intrahepatic accumulation have broad effects on metabolic liver functions. (HEPATOLOGY 2017;66:124-135) a 1 -Antitrypsin (AAT) deficiency (AATD) is one of the most common genetic disorders. The Z deficiency allele (p.Glu342Lys) of the SERPINA1 gene is present in 1 in 25 of the north European Caucasian population, of whom 1 in 2,000 to 1 in 3,500 are homozygotes.(1) The Z mutation results in deficiency of the major circulating protease inhibitor AAT predisposing to early-onset panlobular basal emphysema. Concomitantly, it causes retention of the protein within hepatocytes that is associated with neonatal hepatitis, cirrhosis, and hepatocellular carcinoma (HCC).(1,2) The natural history of liver disease due to homozygous Z allele is highly variable, and approximately 20% of homozygous ZZ newborns develop symptomatic cholestatic hepatitis.(3) Approximately 50% of ZZ infants and children are likely to develop Abbreviations: AAT, a 1 -antitrypsin; AATD, AAT deficiency; ARG1, arginase 1; ATZ, AAT encoded by the Z allele; CDH1, cadherin-1;

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Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Down‐regulation of hepatocyte nuclear factor‐4α and defective zonation in livers expressing mutant Z α1‐antitrypsin

et al. 2017

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“…The number of globules was similarly reduced in mice of the same age that had been injected with only saline. Such an age-dependent decrease in globules was previously seen in PiZ mice (29). However, globules in the saline group animals were 2.75-fold larger and comprised 2.54-fold more area of the liver than those in mice treated with ARC-AAT (Figure 2, D, F, and G).…”

Section: Resultssupporting

confidence: 74%

Development of an RNAi therapeutic for alpha-1-antitrypsin liver disease

Wooddell¹,

Blomenkamp²,

Peterson³

et al. 2020

JCI Insight

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“…reproduce findings seen in progressive familial intrahepatic cholestasis (33), while PiZ mice mimic the alterations seen in subjects with alpha1-antitrypsin deficiency (34,35).…”

Section: Accepted Manuscriptmentioning

confidence: 57%