Ursodeoxycholyl lysophosphatidylethanolamide inhibits cholestasis- and hypoxia-induced apoptosis by upregulating antiapoptosis proteins

Abstract

An increase of toxic bile acids such as glycochenodeoxycholic acid occurs during warm ischemia reperfusion causing cholestasis and damage in hepatocytes and intrahepatic biliary epithelial cells. We aim to test antiapoptosis effects of ursodeoxycholyl lysophosphatidylethanolamide under cholestatic induction by glycochenodeoxycholic acid treatment of mouse hepatocytes and hypoxia induction by cobalt chloride treatment of intrahepatic biliary epithelial cancer Mz-ChA-1cell line. Such treatments caused marked increases in apoptosis as evidenced by activation of caspase 3, caspase 8 and poly (ADP-ribose) polymerase-1. Co-treatment with ursodeoxycholyl lysophosphatidylethanolamide significantly inhibited these increases. Interestingly, ursodeoxycholyl lysophosphatidylethanolamide was able to increase expression of antiapoptotic cellular FLICE-inhibitory protein in both cell types. Ursodeoxycholyl lysophosphatidylethanolamide also prevented the decreases of myeloid cell leukemia sequence-1 protein in both experimental systems, and this protection was due to ursodeoxycholyl lysophosphatidylethanolamide's ability to inhibit ubiquitination-mediated degradation of myeloid cell leukemia sequence-1, and to increase the phosphorylation of GSK-3b. In addition, ursodeoxycholyl lysophosphatidylethanolamide was able to prevent the decreased expression of another antiapoptotic cellular inhibitor of apoptosis 2 in cobalt chloride-treated Mz-ChA-1 cells. Hence, ursodeoxycholyl lysophosphatidylethanolamide mediated cytoprotection against apoptosis during toxic bile-acid and ischemic stresses by a mechanism involving accumulation of cellular FLICE-inhibitory protein, myeloid cell leukemia sequence-1 and cellular inhibitor of apoptosis 2 proteins. Ursodeoxycholyl lysophosphatidylethanolamide may thus be used as an agent to prevent hepatic ischemia reperfusion.

The effects of ursodeoxycholic acid on sepsis-induced cholestasis management in an animal model

“…The effect of UDCA on apoptosis inhibition has been reportedly mediated by the upregulation of various anti-apoptotic proteins, such as FLICE-inhibitory protein, myeloid leukaemia sequence-1 protein, and cellular inhibitor of apoptosis-2 protein. 24 …”

Elevated cholesterol levels have a poor prognosis in a cholestasis scenario

“…In cholestasis, hydrophilic BAs decrease; therefore, protecting proteins such as NFκB, cFLIP, CIAP2, and MCL‐1 are inhibited, decreasing bile flow and cholesterol solubility furthermore increasing the NOSs. Alterations in lipid metabolism contribute to the pathogenesis and progression of cholestatic liver disease . Meanwhile, cholestasis enhances the expression of various transporters, such as BSEP, ABCB4, SHP, ABCA1, and the heterodimer ABCG5/ABCG8, which increase the excretion of cholesterol from the liver to the serum, affecting the bile flow, increasing toxic BAs concentration, rising inflammation, and liver damage (Figure ) …”

“…On the other hand, in an HepG2 and primary hepatocyte cellular model, the UDCA‐lysophosphatidylethanolamide (UDCA‐LPE) complex is effective in apoptosis inhibition, affecting both intrinsic and extrinsic pathways, inducing survival signals such as nuclear factor kappa‐light‐chain‐enhancer of activated B cells in part by accumulation of antiapoptotic cellular FLICE‐like inhibitory protein (cFLIP), cellular inhibitor of apoptosis 2 (CIAP2), and myeloid cell leukemia sequence 1 (Mcl‐1); moreover UDCA‐LPE inhibits the proteasomal degradation of Mcl‐1 via phosphoinositide 3‐kinase/protein kinase B (PI3K/Akt) which inhibits downstream Glycogen synthase kinase‐3 alpha and beta (GSK3α/β) signaling pathways, also by the activation of stearoyl‐CoA desaturase‐1 (SCD‐1), an enzyme that converts saturated fatty acids to monosaturated fatty acids, being involved in alterations of fatty acid composition . On the other hand, Akiyama et al.…”

Long-term hypoxia exposure enhanced IGFBP-3 protein synthesis and secretion resulting in cell apoptosis in H9c2 myocardial cells

“…When the myocardium is deprived of blood, a process involving ischemia, infarction and myocardial remodeling is initiated that leads to myocardial hypoxia (Lee et al, 2000). Evidence from several studies indicated that hypoxia can trigger apoptosis in cardiomyocytes (Sellinger et al, 2015;Yan et al, 2014). Our previous studies showed that long-term intermittent hypoxia could result in eccentric cardiac hypertrophy in rats (Chen et al, 2007) and induce both mitochondrial-dependent apoptotic and Fas death receptor-dependent apoptotic pathways in rat hearts (Lee et al, 2007).…”