No abstract

Activation of death receptors and mitochondrial damage are well-described common apoptotic pathways. Recently, a novel pathway via endoplasmic reticulum (ER) stress has been reported. We assessed the role of tauroursodeoxycholic acid (TUDCA) in inhibition of caspase-12 activation and its effect on calcium homeostasis in an ER stress-induced model of apoptosis. The human liver-derived cell line, Huh7, was treated with thapsigargin (TG) to induce ER stress. Typical morphologic changes of ER stress preceded development of apoptotic changes, including DNA fragmentation and cleavage of poly (adenosine diphosphateribose) polymerase (PARP), as well as activation of caspase-3 and -7. Elevation of intracellular calcium levels without loss of mitochondrial membrane potential (MMP) was shown using Fluo-3/Fura-red labeling and flow cytometry, and confirmed by induction of Bip/GRP78, a calcium-dependent chaperon of ER lumen. These changes were accompanied by procaspase-12 processing. TUDCA abolished TG-induced markers of ER stress; reduced calcium efflux, induction of Bip/GRP78, and caspase-12 activation; and subsequently inhibited activation of effector caspases and apoptosis. In conclusion, we propose that mitochondria play a secondary role in ER-mediated apoptosis and that TUDCA prevents apoptosis by blocking a calcium-mediated apoptotic pathway as well as caspase-12 activation. This novel mechanism of TUDCA action suggests new intervention methods for ER stress-induced liver disease. (HEPATOLOGY 2002;36:592-601.)

Hepatitis C virus (HCV) has emerged as a major pathogen among patients with human immunodeficiency virus (HIV). Morbidity and mortality were compared among 263 patients with HIV alone, 166 patients with HIV and HCV, and 60 patients with HCV alone (mean duration of follow-up, 2 years and 10 months). No differences in HIV loads and CD4 cells counts were observed between the HIV and HIV/HCV groups. Alanine aminotransferase levels were higher (52 U/L versus 35 U/L; P<.05) and albumin levels were lower (3.5 g/dL versus 3.8 g/dL; P <.02) among coinfected patients than they were among patients with HIV alone. Liver decompensation developed in 10% of patients with HIV/HCV coinfection. In contrast, no liver-related deaths or decompensation occurred in patients without coinfection (P<.05). Of the patients with HIV alone, 7% died, compared with 11% of the coinfected patients (P<.02); 47% of the deaths in the latter group were due to liver-related causes. In summary, HCV infection causes increased morbidity and mortality in patients with HIV infection.