Involvement of endoplasmic reticulum in glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes

Some Findings on Apoptosis in Hepatocytes

“…Patel and his colleagues reported for the first time that low concentration of glycodeoxycholic acid induced apoptosis in hepatocytes, and pointed out that bile acids may induce necrosis at higher concentrations and apoptosis at lower concentrations in hepatocytes [25,26]. Furthermore, Sokol and his colleagues reported that hydrophobic bile acid induced lipid peroxidation and mitochondrial dysfunction via enhancement of mitochondrial membrane permeability [27], and we ourselves also reported mitochondria-mediated time-and concentration-dependent apoptotic cell death and endoplasmic reticulum (ER) stress-mediated apoptosis of hepatocytes induced by GCDCA [28,29].…”

“…We ourselves studied the effects of GCDCA treatment in hepatocytes, and found that when the culture medium contained Ca 2+ , persistent increase in intracellular Ca 2+ was observed while only transient increase in intracellular Ca2+ was observed when cells were cultured in Ca 2+ free medium, showing that GCDCA promotes Ca 2+ influx from extracellular matrix and release of Ca 2+ from ER. Activations of calpain and caspase-12 due to the increase in intracellular Ca 2+ were also observed, and we reported that GCDCA induces apoptosis mediated by ER stress [29]. Furthermore, we reported the correlation between ER stress associated with GCDCA and caspase-8 activation.…”

Bile acids: regulation of apoptosis by ursodeoxycholic acid

“…Finally, although mitochondrial cytochrome c release is FADD/caspase-8 dependent during hepatocyte apoptosis, pro-apoptotic bile acids, at concentrations similar to those found in cholestatic liver injury, are still capable of inducing apoptosis by the intrinsic pathway when death receptor activation is inhibited ( 63 ). Recently, apoptosis via the endoplasmic reticulum (ER) stress-mediated pathway was also found in GCDCA-induced apoptosis of liver cells, although to a lesser extent ( 64,65 ). Treatment with the bile acid resulted in ER-related Ca 2+ release, increased calpain and caspase-12 activities, and induction of the ER stress biomarkers Bip and Chop mRNA expression levels.…”

Endoplasmic-Reticulum Calcium Depletion and Disease

“…Glycochenodeoxycholic acid depletes ER Ca 2þ and induces a UPR and apoptosis (Tsuchiya et al 2006). It is unclear to what extent the decreasing [Ca 2þ ] ER directly contributes to the pathology.…”