Background & Aims-Glycochenodeoxycholate (GCDC) and taurolithocholate (TLC) are hepatotoxic and cholestatic bile salts, whereas tauroursodeoxycholate (TUDC) is cytoprotective and anticholestatic. Yet they all act, in part, through phosphatidylinositol-3-kinase(PI3K)-dependent mechanisms ("PI3K-paradox"). Hepatocytes express three catalytic PI3K Class I isoforms (p110α/ β/γ), specific functions of which, in liver, are unclear. In other cell types, p110γ is associated with detrimental effects. To shed light on the PI3K enigma, we determined whether hydrophobic and hydrophilic bile salts differentially activate distinct p110 isoforms in hepatocytes, and whether p110γ mediates bile salt-induced hepatocyte cell death.

Gates A, Hohenester S, Anwer MS, Webster CRL. cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 ␤/␣ in rat hepatocytes.

Background/Aim-Adherence to an extracellular matrix (ECM) rescues hepatocytes from apoptosis, but how hepatocytes adhered to different ECM respond to apoptotic and cytoprotective stimuli is unknown.

Lipopolysaccharide (LPS) is known to damage hepatocytes by cytokines released from activated Kupffer cells, but the ancillary role of LPS as a direct hepatotoxin is less well characterized. The aim of this study was to determine the direct effect of LPS on hepatocyte viability and the underlying signaling mechanism. Rat hepatocyte cultures treated overnight with LPS (500 ng/mL) induced apoptosis as monitored morphologically (Hoechst 33258) and biochemically (cleavage of caspase 3 and 9 and the appearance of cytochrome C in the cytoplasm). LPS-induced apoptosis was additive to that induced by glycochenodeoxycholate or Fas ligand, was associated with activation of c-Jun N-terminal kinase B (JNK) and p38 mitogen-activated protein kinases (MAPK), and inhibition of protein kinase (AKT). Inhibition of JNK by SP600125, but not of p38 MAPK by SB203580 attenuated LPS-induced apoptosis, indicating JNK dependency. CPT-2-Me-cAMP, an activator of cAMP-GEF, decreased apoptosis due to LPS alone or in combination with glycochenodeoxycholate or Fas ligand. CPT-2-Me-cAMP also prevented LPS-induced activation of JNK and inhibition of AKT Taken together, these results suggest that LPS can induce hepatocyte apoptosis directly in vitro in a JNK-dependent manner and activation of cAMP-GEF protects against the LPS-induced apoptosis most likely by reversing the effect of LPS on JNK and AKT