Tauroursodeoxycholic acid inhibits apoptosis induced by Z alpha‐1 antitrypsin via inhibition of bad

• Published in: Hepatology (Baltimore, Md.) Vol. 46; no. 2; pp. 496 - 503
• Main Authors: Miller, Stanley D.W., Greene, Catherine M., McLean, Caitriona, Lawless, Matthew W., Taggart, Clifford C., O'Neill, Shane J., McElvaney, Noel G.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-08-2007; Wiley
• Subjects: alpha 1-Antitrypsin - physiology; Apoptosis - drug effects; bcl-Associated Death Protein - antagonists & inhibitors; bcl-Associated Death Protein - metabolism; Biological and medical sciences; Caspase 3 - metabolism; Caspases, Initiator - physiology; Cells, Cultured; Cytochromes c - secretion; Errors of metabolism; Humans; Medical sciences; Metabolic diseases; Phosphatidylinositol 3-Kinases - physiology; Phosphorylation; Proteins and glycoproteins; Taurochenodeoxycholic Acid - pharmacology; Prognosis; Enzyme; Pathogenesis; Glycoprotein; Caspase; Metabolic diseases; Hepatic disease; Tauroursodeoxycholic acid; Enzymopathy; In vitro; Survival; Stress; α1-Antitrypsin; Genetic disease; Peptidases; Treatment; Digestive diseases; Hydrolases; α1-Antitrypsine deficiency; Apoptosis
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.21689

Z alpha‐1 antitrypsin (AAT) deficiency is a genetic disease associated with accumulation of misfolded AAT in the endoplasmic reticulum (ER) of hepatocytes. ZAAT‐expressing cells display ER stress responses including nuclear factor kappaB activation and apoptosis. Using an in vitro model of ZAAT ER accumulation, we investigated the mechanism of ZAAT‐mediated ER‐induced apoptosis and evaluated methods to inhibit this process. Here we demonstrate that expression of ZAAT, but not normal MAAT, in HEK293 cells leads to cleavage and activation of caspase‐4 and induces apoptosis that is characterized by activation of caspase‐3 and caspase‐7 and DNA fragmentation. Similar effects are also induced using the ER agonist thapsigargin. A caspase‐4–specific short interfering RNA (siRNA) does not impair ZAAT‐induced caspase‐3/7 activation or cell death in these cells. However, inhibition studies performed using tauroursodeoxycholic acid (TUDCA) demonstrate its ability to inhibit caspase‐4 and caspase‐3/7 activation, mitochondrial cytochrome c release, and caspase‐3 cleavage induced by ZAAT and to promote cell survival. The mechanism by which TUDCA (tauroursodeoxycholic acid) promotes cell survival in ZAAT‐expressing cells involves phosphorylation and inactivation of the proapoptotic factor Bad. TUDCA is unable to rescue cells from apoptosis or phosphorylate Bad in the presence of LY294002, a selective P‐I‐3‐kinase inhibitor. Conclusion: These data show that caspase‐4 is not essential for ZAAT‐induced apoptosis in HEK293 cells and implicates P‐I‐3‐kinase and Bad as potential therapeutic targets for the liver disease associated with ZAAT deficiency. (HEPATOLOGY 2007.)