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

Geoffrey C. Farrell, Claire Z. Larter, Jing Yun Hou, Rena H. Zhang, Matthew M. Yeh, Jacqueline Williams, Aileen Dela Peňa, Rona Francisco, Sarah R. Osvath, John Brooling, Narcissus Teoh, Lisa M. Sedger

Research output: Contribution to journalArticlepeer-review

108 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)443-452
Number of pages10
JournalJournal of Gastroenterology and Hepatology (Australia)
Issue number3
Publication statusPublished - 2009


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