NDLI: Mallory-Denk Body (MDB) Formation Modulates Ufmylation Expression Epigenetically in Alcoholic Hepatitis (AH) and Non Alcoholic Steatohepatitis (NASH)

Content Provider	PubMed Central
Author	Liu, Hui Gong, Ming French, Barbara A. Jun, Li Tillman, Brittany French, Samuel W.
Copyright Year	2014
Abstract	Promoter CpG island hypermethylation is an important mechanism for inactivating key cellular enzymes that mediate epigenetic processes in hepatitis-related hepatocellular carcinoma (HCC). The ubiquitin-fold modifiers 1 (Ufm1) conjugation pathway (Ufmylation) plays an essential role in protein degradation, protein quality control and signal transduction. Previous studies showed that the Ufmylation pathway was down regulated in alcoholic hepatitis (AH), non alcoholic steatohepatitis (NASH) and in mice fed DDC, resulting in the formation of Mallory-Denk bodies (MDBs). In this study, we further discovered that betaine, a methyl donor, fed together with DDC significantly prevents the increased expression of Ufmylation in drug-primed mice fed DDC. Betaine significantly prevented transcript silencing of Ufm1, Uba5 and UfSP1 where MDBs developed and also prevented the increased expression of FAT10 and LMP7 caused by DDC re-fed mice. Similar down regulation of Ufmylation was observed in multiple AH and NASH biopsies which had formed MDBs. The DNA methylation levels of Ufm1, Ufc1 and UfSP1 in the promoter CpG region were significantly increased both in AH and NASH patients compared to normal subjects. DNA (cytosine-5-)-methyltransferase 1 (DNMT1) and DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) mRNA levels were markedly up regulated in AH and NASH patients, implying that the maintenance of Ufmylation methylation might be mediated by DNMT1 and DNMT3B together. These data show that MDB formation results from Ufmylation expression epigenetically in AH and NASH patients. Promoter CpG methylation may be a major mechanism silencing Ufmylation expression.
Related Links	http://dx.doi.org/10.1016/j.yexmp.2014.10.001
Ending Page	483
Page Count	7
Starting Page	477
File Format	PDF
ISSN	00144800
e-ISSN	10960945
Journal	Experimental and molecular pathology
Issue Number	3
Volume Number	97
Language	English
Publisher Date	2014-12-01
Access Restriction	Open
Subject Keyword	Pathology and Forensic Medicine Clinical Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Clinical Biochemistry Molecular Biology Pathology and Forensic Medicine

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