title: Inhibition of SIRT2 suppresses hepatic fibrosis.
abstract: Liver fibrosis can progress to cirrhosis and result in serious complications of liver disease. The pathogenesis of liver fibrosis involves the activation of hepatic stellate cells (HSCs), the underlying mechanisms of which are not fully known. Emerging evidence suggests that the classic histone deacetylases play a role in liver fibrosis, but the role of another subfamily of histone deacetylases, the sirtuins, in the development of hepatic fibrosis remains unknown. In this study, we found that blocking the activity of sirtuin 2 (SIRT2) by using inhibitors or shRNAs significantly suppressed fibrogenic gene expression in HSCs. We further demonstrated that inhibition of SIRT2 results in the degradation of c-MYC, which is important for HSC activation. In addition, we discovered that inhibition of SIRT2 suppresses the phosphorylation of ERK, which is critical for the stabilization of c-MYC. Moreover, we found that Sirt2 deficiency attenuates the hepatic fibrosis induced by carbon tetrachloride (CCl4) and thioacetamide (TAA). Furthermore, we showed that SIRT2, p-ERK, and c-MYC proteins are all overexpressed in human hepatic fibrotic tissues. These data suggest a critical role for the SIRT2/ERK/c-MYC axis in promoting hepatic fibrogenesis. Inhibition of the SIRT2/ERK/c-MYC axis represents a novel strategy to prevent and to potentially treat liver fibrosis and cirrhosis.
authors.affiliation: Departments of Surgery.
authors.forename: Maribel
authors.initials: M
authors.lastname: Arteaga
authors.affiliation: Departments of Surgery.
authors.forename: Na
authors.initials: N
authors.lastname: Shang
authors.affiliation: Medicine.
authors.forename: Xianzhong
authors.initials: X
authors.lastname: Ding
authors.affiliation: Medicine.
authors.forename: Sherri
authors.initials: S
authors.lastname: Yong
authors.affiliation: Medicine.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Cotler
authors.affiliation: Pathology.
authors.forename: Mitchell F
authors.initials: MF
authors.lastname: Denning
authors.affiliation: Pharmacology, and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Molecular/Cellular Physiology, Oncology Institute, Loyola University Chicago, Maywood, Illinois; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Breslin
authors.affiliation: Institute of Biochemistry and Molecular Biology, RWTH Aachen University, Aachen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: Departments of Surgery, wqiu@luc.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Qiu
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D016022:Case-Control Studies; D002460:Cell Line; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D055166:Hepatic Stellate Cells / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics* / Q000378:metabolism; D013853:Thioacetamide / Q000633:toxicity
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D013853:Thioacetamide; D002251:Carbon Tetrachloride; D048049:Extracellular Signal-Regulated MAP Kinases; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2
keywords: COL1A1; ECM; hepatic stellate cell; histone deacetylases; α-SMA