Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression.
OBJECTIVE
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-alpha-receptor (TNF-R)1, TNF-R2, Fas, and TNFalpha-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 approximately 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.
Farrell
Geoffrey C
GC
Gastroenterology & Hepatology Unit, The Canberra Hospital and Australian National University Medical School, Garran, Australian Capital Territory, Australia. geoff.farrell@act.gov.au
Larter
Claire Z
CZ
Hou
Jing Yun
JY
Zhang
Rena H
RH
Yeh
Matthew M
MM
Williams
Jacqueline
J
dela Pena
Aileen
A
Francisco
Rona
R
Osvath
Sarah R
SR
Brooling
John
J
Teoh
Narcissus
N
Sedger
Lisa M
LM
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D002796:Choline Deficiency / Q000150:complications; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009752:Nutritional Status; D012333:RNA, Messenger / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism
D051023:BH3 Interacting Domain Death Agonist Protein; C494812:Bcl2l1 protein, mouse; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; C491899:Fas protein, mouse; D012333:RNA, Messenger; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; C505640:Tnfrsf10b protein, mouse; C506236:Tnfrsf1a protein, mouse; C469947:Tnfrsf23 protein, mouse; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D019014:fas Receptor; D007334:Insulin-Like Growth Factor I; D008715:Methionine; D000410:Alanine Transaminase; C505409:Casp3 protein, mouse; D053148:Caspase 3