Roles for C16-ceramide and Sphingosine 1-Phosphate in Regulating Hepatocyte Apoptosis in Response to Tumor Necrosis Factor-α

Osawa, Yosuke; Uchinami, Hiroshi; Bielawski, Jacek; Schwabe, Robert F.; Hannun, Yusuf A.; Brenner, David A.

doi:10.1074/jbc.m503002200

Cited by 212 publications

(166 citation statements)

References 48 publications

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“…Refs. [41][42][43]. Although Cer can be generated from SM in practically all cellular compartments via the activation of sphingomyelinases (SMases), it is the mitochondrial Cer that is associated with apoptosis, the Cer generated in other cellular compartments having no effect on this death mechanism (44).…”

Section: Discussionmentioning

confidence: 99%

Ceramides and Sphingomyelins with High Proportions of Very Long-chain Polyunsaturated Fatty acids in Mammalian Germ Cells

Furland

Zanetti

Oresti

et al. 2007

Journal of Biological Chemistry

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Very long-chain polyunsaturated fatty acids (VLCPUFA) have previously been shown to be components of sphingomyelin (SM) of mammalian testis and spermatozoa. Here we examined the fatty acids of testicular ceramide (Cer) in comparison with those of SM in some mammals with a special focus on the rat testis. In bull, cat, dog, rabbit, mouse, and rat, VLCPUFA were found in both testicular lipids, Cer having a higher percentage of VLCPUFA than SM. Rat testis had the highest percentage of VLCPUFA in both lipids, the major ones being 28:4n-6 and 30:5n-6. VLCPUFA-containing SM and Cer occurred in cells located in the seminiferous tubules, where germ cells had a higher percentage of these species than Sertoli cells. Seminiferous tubule fractionation showed that SM and Cer of mitochondria and lysosomes had mostly saturates and negligible VLCPUFA, the latter being important in the SM and Cer of microsomes and other membrane fractions. VLCPUFA were absent from the SM and Cer of rat prepuberal testis, increased with the onset of spermatogenesis to account for nearly 15 and 40% of the total fatty acids of testicular SM and Cer, respectively, remained at those levels throughout the adult life of fertile rats and tended to decrease at advanced ages. Four conditions that lead to selective death of germ cells in vivo, namely experimental cryptorchidism, post-ischemic reperfusion, focalized x-ray irradiation and treatments with the antineoplasic drug doxorubicin, caused the VLCPUFA to disappear from the testicular SM and Cer of adult fertile rats, showing that these lipids are specific traits of spermatogenic cells.

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Section: Discussionmentioning

confidence: 99%

Ceramides and Sphingomyelins with High Proportions of Very Long-chain Polyunsaturated Fatty acids in Mammalian Germ Cells

Furland

Zanetti

Oresti

et al. 2007

Journal of Biological Chemistry

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“…17,18,22 In line with this, it has been shown that ACDase overexpression prevented TNF-induced death in L929 cells, 21 whereas NCDase transfection protected rat hepatocytes from TNF-induced cell death through ASMase activation. 44 Ceramide Generation Through ASMase Contributes to Hepatocellular Death. The next question we addressed was whether ceramide signals hepatocellular death and whether hepatic I/R injury would be modulated by the generation of ceramide.…”

Section: Discussionmentioning

confidence: 99%

Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury

et al. 2006

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The molecular mechanisms of hepatic ischemia/reperfusion (I/R) damage are incompletely understood. We investigated the role of ceramide in a murine model of warm hepatic I/R injury. This sphingolipid induces cell death and participates in tumor necrosis factor (TNF) signaling. Hepatic ceramide levels transiently increased after the reperfusion phase of the ischemic liver in mice, because of an early activation of acidic sphingomyelinase (ASMase) followed by acid ceramidase stimulation. In vivo administration of an ASMase inhibitor, imipramine, or ASMase knockdown by siRNA decreased ceramide generation during I/R, and attenuated serum ALT levels, hepatocellular necrosis, cytochrome c release, and caspase-3 activation. ASMase-induced ceramide generation activated JNK resulting in Bim L phosphorylation and translocation to mitochondria, as the inhibition of ASMase by imipramine prevented these events. In contrast, blockade of ceramide catabolism by N-oleyolethanolamine (NOE), a ceramidase inhibitor, enhanced ceramide levels and potentiated I/R injury compared with vehicle-treated mice. Pentoxifylline treatment prevented TNF upregulation and ASMase activation. Furthermore, 9 of 11 mice treated with imipramine survived 7 days after total liver ischemia, compared with 4 of 12 vehicle-treated mice, whereas 8 of 8 NOE-treated mice died within 2 days of total liver ischemia. In conclusion, ceramide generated from ASMase plays a key role in I/R-induced liver damage, and its modulation may be of therapeutic relevance.

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“…Hepatocytes were then isolated by a nonrecirculating in situ collagenase perfusion of the liver through cannulation of the inferior vena cava as previously described. 12,13 After isolation, hepatocytes were washed 3 times and centrifuged at 50g for 1 minute. Cell viability was consistently 90% as determined by trypan blue exclusion.…”

Section: Methodsmentioning

confidence: 99%

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

et al. 2007

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Alpha-1 antitrypsin (␣1-AT) deficiency is the most common genetic cause of liver disease in children. The homozygous ␣1-ATZ mutation (PiZZ) results in significant liver disease in 10% of all affected patients. The ␣1-ATZ mutation also may lead to worse liver injury in the setting of other liver diseases such as cystic fibrosis, nonalcoholic fatty liver disease, and hepatitis C. Although cholestatic injury is common to many forms of liver disease, its effect on the PiZZ phenotype is unknown. To elucidate the interplay of cholestasis and the PiZZ phenotype, we performed bile duct ligation (BDL) on C57BL/6 mice possessing a transgenic ␣1-ATZ mutation and littermate controls. PiZ transgenic mice undergoing BDL developed more liver fibrosis by quantification of Sirius red staining (P ‫؍‬ 0.0003) and hydroxyproline (P ‫؍‬ 0.007) than wildtype mice after BDL. More activated hepatic stellate cells (HSCs) and apoptotic cells also were observed in the PiZ BDL model. Quantitative real time polymerase chain reaction (PCR) of the endoplasmic reticulum (ER) stress markers CHOP and GRP78 were 4-fold and 2-fold more up-regulated, respectively, in PiZ BDL mice when compared with wild-type BDL mice (P ‫؍‬ 0.02, P ‫؍‬ 0.02). Increased apoptosis was also noted in PiZ BDL mice by terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) and cleaved caspase-3 histological staining. Conclusion: PiZ transgenic mice are more susceptible to liver fibrosis induced by cholestasis from BDL. Cholestasis therefore may lead to increased fibrosis in ␣1-AT deficiency, and the ␣1-ATZ mutation may act as a modifier gene in patients with concurrent cholestatic liver diseases such as cystic fibrosis.

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Roles for C16-ceramide and Sphingosine 1-Phosphate in Regulating Hepatocyte Apoptosis in Response to Tumor Necrosis Factor-α

Cited by 212 publications

References 48 publications

Ceramides and Sphingomyelins with High Proportions of Very Long-chain Polyunsaturated Fatty acids in Mammalian Germ Cells

Ceramides and Sphingomyelins with High Proportions of Very Long-chain Polyunsaturated Fatty acids in Mammalian Germ Cells

Critical role of acidic sphingomyelinase in murine hepatic ischemia-reperfusion injury

Alpha-1 antitrypsin Z protein (PiZ) increases hepatic fibrosis in a murine model of cholestasis

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