Neonatal Hepatitis Induced by α ₁ -Antitrypsin: a Transgenic Mouse Model

Abstract

Transgenic mouse lineages were established that carry the normal (M) or mutant (Z) alleles of the human alpha 1-antitrypsin (alpha 1-Pi) gene. All of the alpha 1-Pi transgenic mice expressed the human protein in the liver, cartilage, gut, kidneys, lymphoid macrophages, and thymus. The human M-allele protein was secreted normally into the serum. However, the human Z-allele protein accumulated in several cell types, but particularly in hepatocytes, and was found in serum in tenfold lower concentrations than the M-allele protein. Mice in one lineage carrying the mutant Z allele expressed high levels of human alpha 1-Pi RNA and displayed significant runting (50% of normal weight) in the neonatal period. This lineage was found to have alpha 1-Pi-induced liver pathology in the neonatal period, concomitant with the accumulation of human Z protein in diastase-resistant cytoplasmic globules that could be revealed in the Periodic acid-Schiff reaction (PAS). The phenotype of mice in the strain expressing high levels of the Z allele is remarkably similar to human neonatal hepatitis, and this strain may prove to be a useful animal model for studying this disease.

Molecular Pathogenesis of Liver Disease in α1–Antitrypsin Deficiency

“…The proteasome may initiate a process which is completed by other enzymes within tion in the neonatal period. 9 There are also nodular clusters of altered hepatocytes that lack a 1 -AT-immunoreactivity the ER membrane or within the ER lumen.…”

Alpha-1-Antitrypsin Deficiency: A New Paradigm for Hepatocellular Carcinoma in Genetic Liver Disease *

“…The strongest evidence for the gain-of-toxic function mechanism is the development of liver disease in mice transgenic for mutant human ␣1ATZ. 3,5 Because normal levels of endogenously derived anti-elastases are present in these mice, the liver injury cannot be attributed to a loss-of-function mechanism.…”

“…1). Studies of the Z#2 mouse model, generated by using a human ␣1ATZ genomic fragment as transgene, 3 have shown that these globuledevoid cells occupy an increasing proportion of the liver as the animal ages and ultimately become the site of adenomas and carcinomas. 4 In more recent studies using the PiZ mouse model, another transgenic mouse created with a human ␣1ATZ genomic fragment, 5 we have shown that there is increased proliferation of these globule-devoid hepatocytes at a rate that is directly proportional to the number of globule-containing hepatocytes.…”

Autophagic disposal of the aggregation-prone protein that causes liver inflammation and carcinogenesis in α-1-antitrypsin deficiency

“…The most compelling evidence for the gain-of-toxic function mechanism comes from the observation that mice transgenic for the mutant human ATZ gene develop hepatic inflammation and carcinomas together with the characteristic intrahepatocytic globules. 10,11 These mice have normal levels of endogenous anti-proteases and so the liver disease must be attributable to a gain-of-toxic function mechanism.…”