Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression
Article first published online: 15 FEB 2009
© 2009 The Authors. Journal compilation © 2009 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology
Volume 24, Issue 3, pages 443–452, March 2009
How to Cite
Farrell, G. C., Larter, C. Z., Hou, J. Y., Zhang, R. H., Yeh, M. M., Williams, J., Dela Peňa, A., Francisco, R., Osvath, S. R., Brooling, J., Teoh, N. and Sedger, L. M. (2009), Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression. Journal of Gastroenterology and Hepatology, 24: 443–452. doi: 10.1111/j.1440-1746.2009.05785.x
- Issue published online: 23 MAR 2009
- Article first published online: 15 FEB 2009
- Accepted for publication 15 December 2008.
- cell death pathways;
- methionine and choline deficiency;
- TNF receptors;
- insulin-like growth factor-1;
- TRAIL-R killer/DR5;
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.