title: Ufmylation and FATylation pathways are downregulated in human alcoholic and nonalcoholic steatohepatitis, and mice fed DDC, where Mallory-Denk bodies (MDBs) form.
abstract: We previously reported the mechanisms involved in the formation of Mallory-Denk bodies (MDBs) in mice fed DDC. To further provide clinical evidence as to how ubiquitin-like protein (Ubls) modification, gene transcript expression in Ufmylation and FATylation were investigated in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies and frozen liver sections from DDC re-fed mice were used. Real-time PCR analysis showed that all Ufmylation molecules (Ufm1, Uba5, Ufc1, Ufl1 and UfSPs) were significantly downregulated, both in DDC re-fed mice livers and patients' livers where MDBs had formed, indicating that gene transcript changes were limited to MDB-forming livers where the protein quality control system was downregulated. FAT10 and subunits of the immunoproteasome (LMP2 and LMP7) were both upregulated as previously shown. An approximate 176- and 5-fold upregulation (respectively) of FAT10 was observed in the DDC re-fed mice liver and in the livers of human alcoholic hepatitis with MDBs present, implying that there was an important role played by this gene. The FAT10-specific E1 and E2 enzymes Uba6 and USE1, however, were found to be downregulated both in patients' livers and in the liver of DDC re-fed mice. Interestedly, the downregulation of mRNA levels was proportionate to MDB abundance in the liver tissues. Our results show the first systematic demonstration of transcript regulation of Ufmylation and FATylation in the liver of patients who form MDBs, where protein quality control is downregulated. This was also shown in the livers of DDC re-fed mice where MDBs had formed.
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90509, USA.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90509, USA.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90509, USA.
authors.forename: B
authors.initials: B
authors.lastname: Tillman
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90509, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: French
authors.affiliation: Department of Pathology, LABioMed at Harbor UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90509, USA. Electronic address: sfrench@labiomed.org.
authors.forename: S W
authors.initials: SW
authors.lastname: French
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D015536:Down-Regulation; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006519:Hepatitis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D059609:Mallory Bodies / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D065626:Non-alcoholic Fatty Liver Disease; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000633:toxicity; D050600:SNARE Proteins; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins
chemical_list: C530773:3,5-diethoxycarbonyl-1,4-dihydrocollidine; C512253:FAT10 protein, mouse; D011506:Proteins; D011725:Pyridines; D050600:SNARE Proteins; C502095:UBA5 protein, human; C521757:UBA6 protein, human; C109184:UBD protein, human; C502096:UFC1 protein, human; C502094:UFM1 protein, human; D014452:Ubiquitins; C513664:Ufm1 protein, mouse; C521756:Use1 protein, human; D033921:Vesicular Transport Proteins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D044764:Ubiquitin-Activating Enzymes; C587954:UFL1 protein, human
keywords: FAT10; Mallory–Denk bodies (MDBs); Transcript regulation; Ubiquitin-like (Ubl) modifiers; Ufm1