Accumulation of hepatitis B surface antigen promotes the development of alpha-1 antitrypsin mutation-related liver disease

Introduction: α1-antitrypsin (AAT) constitutes the major serum protease inhibitor that is produced predominantly in hepatocytes. An AAT mutation termed PiZ leads to its polymerization and retention in the endoplasmic reticulum (ER) thereby causing the development of AAT deficiency, the third most common lethal genetic condition in humans. While up to 40% of PiZZ patients develop liver cirrhosis, the phenotype of the disease is highly variable and the factors contributing its development remain unknown. Aims & methodology: To mimic the consequences of a hepatitis B (HBV) infection-related ER stress, we crossbred PiZ mice with animals overexpressing the large hepatitis B surface protein (HBs mice). Livers were evaluated by quantitative RT-PCR, immunoblotting, histological/immunological staining and biochemical assays. Results: HBs-PiZ mice were viable and developed normally. At two months of age, the double transgenic mice displayed a significantly stronger liver injury (ALT: PiZ-HBs 88, HBs 53, PiZ 32, p < 0.05 for both) and a distinct CHOP overexpression. Although both AAT and HBs is retained in the hepatocyte ER, the proteins display a distinct, non-overlapping accumulation pattern. Compared to single transgenic animals, 10 months old PiZ-HBs mice harbour a more pronounced liver fibrosis. At 14 months of age, double transgenic animals demonstrated significantly increased liver-body weight ratio (HBs-AAT 0.08, HBs 0.07, PiZ 0.05, p < 0.05 for both) higher tumor load (Double 141, HBs 36, PiZ 3.7 mm2, p < 0.05 for both) and larger tumor nodules. Conclusions: Our results suggest that accumulation of HBs protein accelerates the development of PiZ-related liver disease.

Corresponding author: Kuscuoglu, Deniz

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