Silibinin Ameliorates O -GlcNAcylation and Inflammation in a Mouse Model of Nonalcoholic Steatohepatitis

• Published in: International journal of molecular sciences 2018-07, Vol.19 (8), p.2165
• Main Authors: Lee, Su Jin, Nam, Min Jung, Lee, Da Eun, Park, Jeen-Woo, Kang, Beom Sik, Lee, Dong-Seok, Lee, Hyun-Shik, Kwon, Oh-Shin
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Antioxidants - administration & dosage; Antioxidants - pharmacology; beta-N-Acetylhexosaminidases - metabolism; Chemical compounds; Choline; Choline Deficiency; Cytoskeleton; Humans; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Keratin; Liver; Liver - pathology; Male; Methionine; Methionine - deficiency; Mice; Mice, Inbred C57BL; NF-kappa B - metabolism; NF-κB protein; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Nutrient deficiency; O-GlcNAcylation; Peroxiredoxin; Peroxiredoxins - metabolism; Pharmacology; Protein disulfide-isomerase; Proteins; Proteomics; RAW 264.7 Cells; Signal transduction; Silibinin; Silymarin - administration & dosage; Silymarin - pharmacology; Two dimensional analysis; Two dimensional models
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms19082165

The mechanisms underlying the progression to non-alcoholic steatohepatitis (NASH) remain to be elucidated. In the present study, we aimed to identify the proteins involved in the pathogenesis of liver tissue inflammation and to investigate the effects of silibinin, a natural polyphenolic flavonoid, on steatohepatitis. We performed comparative proteomic analysis using methionine and choline-deficient (MCD) diet-induced NASH model mice. Eighteen proteins were identified from the two-dimensional proteomic analysis, which are not only differentially expressed, but also significantly improved, by silibinin treatment. Interestingly, seven of these proteins, including keratin cytoskeletal 8 and 18, peroxiredoxin-4, and protein disulfide isomerase, are known to undergo GlcNAcylation modification, most of which are related to structural and stress-related proteins in NASH model animals. Thus, we primarily focused on how the GlcNAc modification of these proteins is involved in the progression to NASH. Remarkably, silibinin treatment alleviates the severity of hepatic inflammation along with -GlcNAcylation in steatohepatitis. In particular, the reduction of inflammation by silibinin is due to the inhibition of the -GlcNAcylation-dependent NF-κB-signaling pathway. Therefore, silibinin is a promising therapeutic agent for hyper- -GlcNAcylation as well as NASH.