title: Chebulic acid prevents hepatic fibrosis induced by advanced glycation end-products in LX-2 cell by modulating Nrf2 translocation via ERK pathway.
abstract: Advanced glycation end-products (AGEs) are formed during normal aging, and at an accelerated rate in metabolic syndrome patients. Nonalcoholic steatohepatitis (NASH) can be caused by the AGEs in plasma, while glyceraldehyde-derived AGEs (glycer-AGEs) are significantly higher in the serum of NASH patients. In this study, we investigated the molecular mechanisms of chebulic acid, isolated from Terminalia chebula Retz., in the inhibition of glycer-AGEs induced production of reactive oxygen species (ROS) and collagen accumulation using the LX-2 cell line. Chebulic acid significantly inhibited the induction of ROS and accumulation of collagen proteins by glycer-AGEs. ERK phosphorylation and total nuclear factor E2-related factor 2 (Nrf2) protein expression were induced by chebulic acid in a dose-dependent manner. Chebulic acid was also found to induce translocation of Nrf2 into the nucleus, which was attenuated by inhibition of ERK phosphorylation through treatment with PD98059. Following translocation of Nrf2, chebulic acid induced the protein expressions of catalytic subunit of γ-glutamylcysteine synthetase and glutathione synthesis. Collagen accumulation was also significantly reduced by chebulic acid treatment. The observed effects of chebulic acid were all inhibited by PD98059 treatment. Taken together, these results suggest that chebulic acid prevents the glycer-AGEs-induced ROS formation of LX-2 cells and collagen accumulation by ERK-phosphorylation-mediated Nrf2 nuclear translocation, which causes upregulation of antioxidant protein production.
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Yun-Chang
authors.initials: YC
authors.lastname: Koo
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Min Cheol
authors.initials: MC
authors.lastname: Pyo
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Mi-Hyun
authors.initials: MH
authors.lastname: Nam
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Chung-Oui
authors.initials: CO
authors.lastname: Hong
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors.forename: Sung-Yong
authors.initials: SY
authors.lastname: Yang
authors.affiliation: Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea. Electronic address: kwangwon@korea.ac.kr.
authors.forename: Kwang-Won
authors.initials: KW
authors.lastname: Lee
mesh_terms: D001578:Benzopyrans / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000633:toxicity; D006801:Humans; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000517:prevention & control; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D020011:Protective Agents / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D024042:Collagen Type I; D017127:Glycation End Products, Advanced; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D020011:Protective Agents; D017382:Reactive Oxygen Species; C572649:chebulic acid; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Advanced glycation end-product; Chebulic acid; Hepatic fibrosis; Human hepatic stellate cell; Nuclear factor E2-related factor