Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

Abstract

Alpha-1 antitrypsin (␣1-AT) deficiency is the most common genetic cause of liver disease in children. The homozygous ␣1-ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The ␣1-ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic ␣1-ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P ‫؍‬ 0.0003) and hydroxyproline (P ‫؍‬ 0.007) than wildtype mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4-fold and 2-fold more up-regulated, respectively, in PiZ BDL mice when compared with wild-type BDL mice (P ‫؍‬ 0.02, P ‫؍‬ 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and cleaved caspase-3 histological staining. Conclusion: PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in ␣1-AT deficiency, and the ␣1-ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis.

IGF-1R Contributes to Stress-Induced Hepatocellular Damage in Experimental Cholestasis

“…35,36 Both oxidative stress and ER stress are induced in cholestatic liver injury. 13,37,38 Malondialdehyde and heme oxygenase-1 expression were both increased in the liver of BDL mice. These changes were not attenuated in LIGFREKO mice, suggesting that the protection conferred by IGF-1R deletion was independent of oxidative stress.…”

Antisense oligonucleotide treatment ameliorates alpha-1 antitrypsin–related liver disease in mice

“…This liver injury signal stimulates less damaged hepatocytes to proliferate to compensate for cell death, which in turn increases the incidence of HCC (26,27). In addition, globule-induced liver injury also leads to fibrosis in these mice (28)(29)(30). Since PiZ hepatocytes are not as healthy as normal hepatocytes due to the presence of globules, they have reduced tolerance to other stress conditions, including fasting, nonsteroidal antiinflammatory drugs, and surgical procedures such as partial hepatectomy (31)(32)(33).…”

CFTR dysfunction predisposes to fibrotic liver disease in a murine model

“…In addition, the human homologue, MDR3, has not been found to be associated with PSC. Other knockout models, including ⌬F508 (17) and exon 10 congenic cftr Ϫ/Ϫ mice (5), variably demonstrate peri-cholangitic inflammation and have only minimal fibrosis after 90 days of age, while, ␣-1 antitrypsin Z mutation by itself is not sufficient to induce fibrosis (23).…”