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Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency
David A Rudnick1, Yunjun Liao, Jae-Koo An
1Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. rudnick_d@kids.wustl.edu
Insights
Alpha-1-antitrypsin (alpha1-AT) deficiency causes pediatric liver disease due to toxic alpha-1-antitrypsin Z (alpha1-ATZ) buildup. Male mice show more liver cell proliferation and injury, linked to testosterone and alpha1-ATZ levels.
Area of Science:
- Hepatology
- Genetics
- Toxicology
Background:
- Alpha-1-antitrypsin (alpha1-AT) deficiency is a common genetic cause of pediatric liver disease.
- Hepatocellular injury arises from the toxic accumulation of mutant alpha-1-antitrypsin Z (alpha1-ATZ) within liver cells.
- The PiZ transgenic mouse model replicates key aspects of human alpha1-AT deficiency for research.
Purpose of the Study:
- To investigate hepatocellular proliferation in response to chronic liver injury in alpha1-AT deficiency.
- To explore gender-specific differences in liver injury and regeneration.
- To assess the impact of intracellular alpha1-ATZ accumulation on hepatocyte proliferation.
Main Methods:
- Utilized the PiZ transgenic mouse model of alpha1-AT deficiency.
- Compared hepatocellular proliferation and caspase 9 activation between male and female PiZ mice and wild-type controls.
- Administered testosterone to female PiZ mice to examine gender-specific effects.
- Analyzed alpha1-AT mRNA and protein expression in the liver.
- Assessed hepatocyte proliferation in globule-containing versus globule-devoid hepatocytes.
Main Results:
- Male PiZ mice exhibited significantly increased hepatocellular proliferation and caspase 9 activation compared to females and wild-type mice.
- Elevated hepatic alpha1-AT mRNA and protein expression were observed in male PiZ mice.
- Testosterone treatment in female PiZ mice mirrored male levels of alpha1-ATZ expression and hepatocellular proliferation.
- Hepatocytes lacking intracellular alpha1-ATZ globules demonstrated a proliferative advantage over those with globules.
- This advantage was relative, as both cell types proliferated comparably after partial hepatectomy.
Conclusions:
- Intracellular retention of mutant alpha1-ATZ acts as a regenerative stimulus, promoting hepatocellular proliferation.
- Gender-specific factors, influenced by testosterone, modulate alpha1-AT expression and subsequent liver injury.
- Hepatocytes without alpha1-ATZ accumulation exhibit a selective proliferative advantage.
- These findings suggest potential applications for hepatocellular transplantation in treating alpha1-AT deficiency and similar metabolic liver diseases.
Abstract:
alpha-1-Antitrypsin (alpha1-AT) deficiency is the most common cause of metabolic pediatric liver disease. Hepatocellular injury is caused by toxicity of the mutant alpha-1-antitrypsin Z (alpha1-ATZ) molecule retained within hepatocytes. In these studies, we used the PiZ transgenic mouse model of alpha1-AT deficiency to examine hepatocellular proliferation in response to chronic liver injury resulting from this metabolic disease. The results showed increased hepatocellular proliferation and caspase 9 activation in male PiZ mice compared with female PiZ and wild-type mice. Hepatic alpha1-AT mRNA and protein expression also were increased in male PiZ mice, suggesting that greater hepatocellular proliferation and caspase activation in males results from increased hepatotoxicity associated with greater intracellular alpha1-ATZ accumulation. Testosterone treatment of female PiZ mice increased alpha1-ATZ expression and hepatocellular proliferation to a level comparable with that in males. In PiZ mice, hepatocytes devoid of intracellular alpha1-AT globules had a proliferative advantage compared with globule-containing hepatocytes. However, this advantage is relative because both globule-containing and globule-devoid hepatocytes exhibited comparable proliferation after partial hepatectomy. In conclusion, these data indicate that intracellular retention of mutant alpha1-ATZ is associated with a regenerative stimulus leading to increased hepatocellular proliferation, that gender-specific signals influence the degree of alpha1-AT expression and associated hepatic injury, and that hepatocytes devoid of alpha1-ATZ have a proliferative advantage over cells that accumulate the mutant protein. This selective proliferation suggests that hepatocellular transplantation may be applicable for treatment of this and other slowly progressive metabolic liver diseases.
