Effect of tauroursodeoxycholic acid on endoplasmic reticulum stress-induced caspase-12 activation

Area of Science:

• Cellular Biology
• Biochemistry
• Pathology

Background:

• Apoptosis commonly involves death receptors and mitochondrial damage.
• Endoplasmic reticulum (ER) stress represents a newly identified apoptotic pathway.
• ER stress-induced apoptosis involves specific molecular signaling cascades.

Purpose of the Study:

• To investigate the role of tauroursodeoxycholic acid (TUDCA) in mitigating ER stress-induced apoptosis.
• To assess TUDCA's effects on caspase-12 activation and calcium homeostasis.
• To elucidate the mechanism of TUDCA in preventing ER-mediated cell death.

Main Methods:

• Utilized the Huh7 human liver cell line.
• Induced endoplasmic reticulum (ER) stress using thapsigargin (TG).
• Assessed apoptotic markers, intracellular calcium levels, mitochondrial membrane potential (MMP), and caspase activation via flow cytometry and molecular labeling.

Main Results:

• Thapsigargin (TG) induced ER stress, characterized by morphologic changes, DNA fragmentation, PARP cleavage, and activation of caspases-3, -7, and -12.
• ER stress led to elevated intracellular calcium without loss of mitochondrial membrane potential (MMP), confirmed by Bip/GRP78 induction.
• TUDCA treatment effectively inhibited TG-induced ER stress markers, reduced calcium efflux, blocked caspase-12 activation, and prevented effector caspase activation and apoptosis.

Conclusions:

• Mitochondria play a secondary role in ER-mediated apoptosis.
• TUDCA prevents apoptosis by inhibiting a calcium-mediated pathway and caspase-12 activation.
• TUDCA offers a novel therapeutic strategy for ER stress-related liver diseases.