SAMe prevents the induction of the immunoproteasome and preserves the 26S proteasome in the DDC-induced MDB mouse model.
Mallory-Denk bodies (MDBs) form in the liver of alcoholic patients. This occurs because of the accumulation and aggregation of ubiquitinated cytokeratins, which hypothetically is due to the ubiquitin-proteasome pathway's (UPP) failure to degrade the cytokeratins. The experimental model of MDB formation was used in which MDBs were induced by refeeding DDC to drug-primed mice. The gene expression and protein levels of LMP2, LMP7 and MECL-1, the catalytic subunits in the immunoproteasome, as well as FAT10, were increased in the liver cells forming MDBs but not in the intervening normal hepatocytes. Chymotrypsin-like activity of the UPP was decreased by DDC refeeding, indicating that a switch from the UPP to the immunoproteasome had occurred at the expense of the 26S proteasome. The failure of the UPP to digest cytokeratins would explain MDB aggregate formation. SAMe prevented the decrease in UPP activity, the increase in LMP2, LMP7, and MECL-1 protein levels and MDB formation induced by DDC. DDC refeeding also induced the TNFalpha and IFNgamma receptors. SAMe prevented the increase in the TNFalpha and IFNgamma receptors, supporting the idea that TNFalpha and IFNgamma were responsible for the up regulation of LMP2, LPM7, and FAT10. These results support the conclusion that MDBs form in FAT10 over-expressing hepatocytes where the up regulation of the immunoproteasome occurs at the expense of the 26S proteasome.
Bardag-Gorce
Fawzia
F
Department of Pathology, LABioMed at Harbor-UCLA Medical Center, Torrance, CA 90509, USA. fgorce@labiomed.org
Oliva
Joan
J
Li
Jun
J
French
Barbara A
BA
French
Samuel W
SW
D000818:Animals; D001483:Base Sequence; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D004095:Dihydropyridines / Q000633:toxicity; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007633:Keratins / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; D004095:Dihydropyridines; C512253:FAT10 protein, mouse; D009097:Multienzyme Complexes; D025801:Ubiquitin; D014452:Ubiquitins; C061879:diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate; C071313:LMP-2 protein; D007633:Keratins; D012436:S-Adenosylmethionine; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex; C490920:Psmb10 protein, mouse; C061553:ATP dependent 26S protease