Journal
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
Volume 24, Issue 3, Pages 443-452Publisher
WILEY
DOI: 10.1111/j.1440-1746.2009.05785.x
Keywords
cell death pathways; methionine and choline deficiency; p53; TNF receptors; insulin-like growth factor-1; TRAIL-R killer; DR5; mitochondria
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Funding
- Australian National Health and Medical Research Council (NHMRC) [358398]
- NHMRC [153889, 418101]
- Australian Postgraduate Research Awards
- The Millennium Institute Stipend Enhancement Grants
- Westmead Hospital Charitable Trust
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We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non-alcoholic steatohepatitis (NASH). To assess extrinsic pathways, we measured hepatic expression of death-inducing cytokine receptors (tumor necrosis factor-alpha-receptor (TNF-R)1, TNF-R2, Fas, and TNF alpha-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. 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 similar 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. 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.
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