Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression

Farrell, GC; Larter, CZ; Hou, JY; Zhang, RH; Yeh, MM; Williams, J; Dela Peňa, A; Francisco, R; Osvath, SR; Brooling, J; Teoh, N; Sedger, LM

Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression

Farrell, GC Larter, CZ Hou, JY Zhang, RH Yeh, MM Williams, J Dela Peňa, A Francisco, R Osvath, SR Brooling, J Teoh, N Sedger, LM

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Publication Type:: Journal Article
Citation:: Journal of Gastroenterology and Hepatology (Australia), 2009, 24 (3), pp. 443 - 452
Issue Date:: 2009-01-01

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Field	Value	Language
dc.contributor.author	Farrell, GC	en_US
dc.contributor.author	Larter, CZ	en_US
dc.contributor.author	Hou, JY	en_US
dc.contributor.author	Zhang, RH	en_US
dc.contributor.author	Yeh, MM	en_US
dc.contributor.author	Williams, J	en_US
dc.contributor.author	Dela Peňa, A	en_US
dc.contributor.author	Francisco, R	en_US
dc.contributor.author	Osvath, SR	en_US
dc.contributor.author	Brooling, J	en_US
dc.contributor.author	Teoh, N	en_US
dc.contributor.author	Sedger, LM https://orcid.org/0000-0003-1009-5683	en_US
dc.date.issued	2009-01-01	en_US
dc.identifier.citation	Journal of Gastroenterology and Hepatology (Australia), 2009, 24 (3), pp. 443 - 452	en_US
dc.identifier.issn	0815-9319	en_US
dc.identifier.uri	http://hdl.handle.net/10453/13712
dc.description.abstract	Background and Aims: We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non-alcoholic steatohepatitis (NASH). Methods: To assess extrinsic pathways, we measured hepatic expression of death-inducing cytokine receptors (tumor necrosis factor-α-receptor (TNF-R)1, TNF-R2, Fas, and TNFα-related apoptosis-inducing ligand-receptor (TRAIL-R) mRNA, TUNEL, caspase 3 activation, liver injury and liver pathology in mice fed a methionine and choline deficient (MCD) diet. For endogenous stress pathways, we determined serum insulin-like growth factor-1 (IGF-1), hepatic p53, Bcl-XL, tBid and p21 expression. Results: Methionine and choline deficient feeding increased alanine aminotransferase (ALT) and apoptosis from day 10, without increases in TNF-R1, TNF-R2, and Fas. However, murine TRAIL receptors, particularly decoyTRAIL-R1/TNFRSFH23 and Killer/DR5 mRNA increased. MCD feeding enhanced hepatic p53 expression, corresponding to ∼50% fall in serum IGF-1, decreased Bcl-XL, enhanced Bid cleavage to tBid, and up-regulation of p21. Nutritional restitution experiments showed that correcting either methionine or choline deficiency suppressed liver inflammation (extrinsic pathway), but failed to correct apoptosis, IGF-1 or p53. Conclusions: Methionine and choline deficiency lower IGF-1 to de-repress p53 during induction of steatohepatitis. The p53 induced by nutritional stress is biologically active in mediating mitochondrial cell death pathways, but may also be responsible for TRAIL receptor expression, thereby linking intrinsic and exogenous apoptosis pathways in NASH. © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.	en_US
dc.relation.ispartof	Journal of Gastroenterology and Hepatology (Australia)	en_US
dc.relation.isbasedon	10.1111/j.1440-1746.2009.05785.x	en_US
dc.subject.classification	Gastroenterology & Hepatology	en_US
dc.subject.mesh	Liver	en_US
dc.subject.mesh	Mitochondria, Liver	en_US
dc.subject.mesh	Animals	en_US
dc.subject.mesh	Mice, Inbred C57BL	en_US
dc.subject.mesh	Mice	en_US
dc.subject.mesh	Fatty Liver	en_US
dc.subject.mesh	Choline Deficiency	en_US
dc.subject.mesh	Disease Models, Animal	en_US
dc.subject.mesh	Alanine Transaminase	en_US
dc.subject.mesh	Methionine	en_US
dc.subject.mesh	Insulin-Like Growth Factor I	en_US
dc.subject.mesh	Receptors, Tumor Necrosis Factor	en_US
dc.subject.mesh	Antigens, CD95	en_US
dc.subject.mesh	Receptors, Tumor Necrosis Factor, Type I	en_US
dc.subject.mesh	Receptors, Tumor Necrosis Factor, Type II	en_US
dc.subject.mesh	RNA, Messenger	en_US
dc.subject.mesh	Apoptosis	en_US
dc.subject.mesh	Gene Expression Regulation	en_US
dc.subject.mesh	Nutritional Status	en_US
dc.subject.mesh	Time Factors	en_US
dc.subject.mesh	Male	en_US
dc.subject.mesh	Tumor Suppressor Protein p53	en_US
dc.subject.mesh	Cyclin-Dependent Kinase Inhibitor p21	en_US
dc.subject.mesh	bcl-X Protein	en_US
dc.subject.mesh	BH3 Interacting Domain Death Agonist Protein	en_US
dc.subject.mesh	Caspase 3	en_US
dc.subject.mesh	Receptors, TNF-Related Apoptosis-Inducing Ligand	en_US
dc.subject.mesh	fas Receptor	en_US
dc.title	Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	24	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1103 Clinical Sciences	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	closed_access
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	24	en_US

Abstract:

Background and Aims: We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non-alcoholic steatohepatitis (NASH). Methods: To assess extrinsic pathways, we measured hepatic expression of death-inducing cytokine receptors (tumor necrosis factor-α-receptor (TNF-R)1, TNF-R2, Fas, and TNFα-related apoptosis-inducing ligand-receptor (TRAIL-R) mRNA, TUNEL, caspase 3 activation, liver injury and liver pathology in mice fed a methionine and choline deficient (MCD) diet. For endogenous stress pathways, we determined serum insulin-like growth factor-1 (IGF-1), hepatic p53, Bcl-XL, tBid and p21 expression. Results: Methionine and choline deficient feeding increased alanine aminotransferase (ALT) and apoptosis from day 10, without increases in TNF-R1, TNF-R2, and Fas. However, murine TRAIL receptors, particularly decoyTRAIL-R1/TNFRSFH23 and Killer/DR5 mRNA increased. MCD feeding enhanced hepatic p53 expression, corresponding to ∼50% fall in serum IGF-1, decreased Bcl-XL, enhanced Bid cleavage to tBid, and up-regulation of p21. Nutritional restitution experiments showed that correcting either methionine or choline deficiency suppressed liver inflammation (extrinsic pathway), but failed to correct apoptosis, IGF-1 or p53. Conclusions: Methionine and choline deficiency lower IGF-1 to de-repress p53 during induction of steatohepatitis. The p53 induced by nutritional stress is biologically active in mediating mitochondrial cell death pathways, but may also be responsible for TRAIL receptor expression, thereby linking intrinsic and exogenous apoptosis pathways in NASH. © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

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http://hdl.handle.net/10453/13712