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Excessive hepatocyte apoptosis is a common event in acute and chronic liver diseases leading to loss of functional liver tissue. Approaches to prevent apoptosis have therefore high potential for the treatment of liver disease. G- protein coupled receptors (GαiPCR) play crucial roles in cell fate (proliferation, cell death) and act through heterotrimeric G-proteins. GaiPCRs have been shown to regulate lipoapoptosis in hepatocytes, but their role in inflammation- or bile acid-induced apoptosis is unknown. Here, we analyzed the effect of inhibiting GaiPCR function, using pertussis toxin (PT), on bile acid- and cytokineinduced apoptosis in hepatocytes. Primary rat hepatocytes, HepG2-rNtcp cells (human hepatocellular carcinoma cells) or H4-II-E cells (rat hepatoma cells) were exposed to glycochenodeoxycholic acid (GCDCA) or tumor necrosis factor-α (TNFα)/ actinomycin D (ActD). PT (50-200 nmol/L) was added 30 minutes prior to the apoptotic stimulus. Apoptosis (caspase-3 activity, acridine orange staining) and necrosis (sytox green staining) were assessed. PT significantly reduced GCDCA- and TNFα/ActD-induced apoptosis in rat hepatocytes (-60%, p<0.05) in a dose-dependent manner (with no shift to necrosis), but not in HepG2-rNtcp cells or rat H-4-II-E cells. The protective effect of pertussis toxin was independent of the activation of selected cell survival signal transduction pathways, including ERK, p38 MAPK, PI3K and PKC pathways, as specific protein kinase inhibitors did not reverse the protective effects of pertussis toxin in GCDCA-exposed hepatocytes. Conclusion: Pertussis toxin, an inhibitor of GaiPCRs, protects hepatocytes, but not hepatocellular carcinoma cells, against bile acid- and cytokine-induced apoptosis and has therapeutic potential as primary hepatoprotective drug, as well as adjuvant in anticancer therapy. [ABSTRACT FROM AUTHOR]

Background: The renin-angiotensin system has an important role in hepatic inflammation and fibrosis. Renin-angiotensin system blockade by angiotensin-converting enzyme (ACE) inhibitors provides some protective effects against hepatic fibrogenesis. Captopril as an ACE inhibitor can decrease inflammatory mediators and attenuate hepatic fibrosis in the livers of bile duct ligated (BDL) rats., Objective: The present study was conducted to investigate the effects of captopril on cytokine production in hepatic fibrosis induced by a bile duct ligation model in rats., Methods: Male rats were divided into four groups including; control, sham operated, BDL, and BDL plus captopril (10 mg/kg/day, orally). After 28 days of treatment, the livers were removed for cytokine analysis. Hepatic interleukin (IL)-10 and tumor necrosis factor (TNF)-α levels were measured., Results: Captopril treatment decreased the hepatic content of the proinflammatory cytokine TNF-α and increased the anti-inflammatory cytokine IL-10., Conclusion: the present study suggests that the protective effect of captopril on hepatic fibrosis is likely to be mediated by cytokine production.