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Phenobarbital induces ATZ globule clearance in a Mouse Model of Alpha‐1 Antitrypsin Deficiency
Author(s) -
Bell Aaron W,
Stoops John,
Oertel Michael,
Michalopoulos George K
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.531.10
Subject(s) - phenobarbital , hepatocyte , hepatocellular carcinoma , chemistry , intracellular , cirrhosis , apoptosis , gene expression , microbiology and biotechnology , mutant , alpha (finance) , medicine , endocrinology , cancer research , gene , biology , biochemistry , in vitro , construct validity , nursing , patient satisfaction
Background Alpha‐1 antitrypsin (α1‐AT) deficiency is the most common genetic cause of pediatric liver disease, which can progress to cirrhosis and hepatocellular carcinoma. Hepatocellular injury is caused by accumulation of the insoluble mutant alpha‐1‐antitrypsin Z (α1‐ATZ) molecule in intracellular globules. Hepatocytes containing these globules (GC) do not proliferate as well as the globule free (GF) hepatocytes in the PiZ (α1‐AT) mouse model. We hypothesized that inducing proliferation by chemical mitogens such as phenobarbital and TCPOBOP would lead to enhanced proliferation of the GF cells that could repopulate the liver and greatly reduce the hepatic stress/damage and/or induce protein clearance mechanisms in GC cells converting them to GF cells. Methods PiZ mice were administered phenobarbitol (0.1% in drinking water) or TCPOBOP (3mg/kg by gavage) at various times and durations. Liver tissue was analyzed for ATZ globule content, proliferation, as well as gene and protein expression changes. Results Continuous or cyclical (1‐week on/1‐week off) administration of phenobarbitol to PiZ mice lead to a significant decrease in ATZ globule content; however, TCPOBOP treatment did not. The size of the ATZ globules was greatly diminished by phenobarbital treatment, indicating likely activation of protein clearance mechanisms that was not seen with TCPOBOP. Ki67 staining showed proliferation in both GC and GF cells with both mitogens. Affymetrix array analysis revealed significant differential gene expression changes in GF and GC cells with and without phenobarbital treatment. Conclusions Proliferation of GF and GC hepatocytes induced by chemical mitogens is not sufficient to induce globule clearance in GC cells. However, phenobarbital induces other changes which results in reduced PiZ globule burden and hepatic toxicity, and may be useful in treating α1‐AT deficiency. Support or Funding Information NIH/NIDDK Grant Number: P01DK096990 New therapies for liver fibrosis and hyper‐proliferation in alpha 1‐AT deficiency. D. Perlmutter‐PI Project 3: Mechanisms of AT expression and hepatocyte hyper‐proliferation in AT deficiency. G. Michalopoulos, PI and A. Bell, Co‐Investigator