Hepatoprotective activities of rosmarinic acid against extrahepatic cholestasis in rats. (October 2017)

• Record Type: Journal Article
• Authors: Lin, Shih-Yi; Wang, Ya-Yu; Chen, Wen-Ying; Liao, Su-Lan; Chou, Su-Tze; Yang, Ching-Ping; Chen, Chun-Jung
• Is Part Of: Food and chemical toxicology. Volume 108(2017)Part A
• Page Start: 214
• Page End: 223
• Publication Date: 2017-10
• Subjects: Cholestasis -- Herbal medicine -- Polyphenol -- Rosmarinic acid; ALT alanine aminotransferase -- ANOVA one-way analysis of variance -- AST aspartate aminotransferase -- BDL bile duct ligation -- CTGF connective tissue growth factor -- ELISA enzyme-linked immunosorbent assay -- EMSA electrophoretic mobility shift assay -- GAPDH glyceraldehyde-3-phosphate dehydrogenase -- γ-GT γ-glutamyl transpeptidase -- H&E hematoxylin/eosin -- HMGB1 high mobility group box-1 -- IL-1β interleukin-1β -- MDA malondialdehyde -- MMP-2 matrix metalloproteinase-2 -- MMP-9 matrix metalloproteinase-9 -- MPO Myeloperoxidase -- ROS reactive oxygen species -- RT-PCR reverse transcriptase polymerase chain reaction -- α-SMA α-smooth muscle actin -- TAK1 transforming growth factor β-activated kinase-1 -- TBARS thiobarbituric acid reactive substances -- TGF-β1 transforming growth factor beta-1 -- TIMP-1 tissue inhibitor of metalloproteinase-1 -- TIMP-2 tissue inhibitor of metalloproteinase-2 -- TLR4 toll-like receptor-4 -- TNF-α tumor necrosis factor-α; Toxicology -- Periodicals; Food poisoning -- Periodicals; Food Poisoning -- Periodicals; Toxicology -- Periodicals; Toxicologie -- Périodiques; Intoxications alimentaires -- Périodiques; Food poisoning; Toxicology; Periodicals; Electronic journals; 615.9
• DOI: 10.1016/j.fct.2017.08.005
• Languages: English
• ISSNs: 0278-6915

Abstract

Abstract: Though rosmarinic acid possesses nutritional, pharmaceutical, and toxic properties and shows therapeutic potential on liver diseases, its therapeutic effects against cholestatic liver diseases have not been proven. Using an extrahepatic cholestasis rat model by bile-duct ligation (BDL), daily oral administration of rosmarinic acid showed improvement effects on liver histology, serum biochemicals, ductular reaction, oxidative stress, inflammation, and fibrosis. Rosmarinic acid alleviated BDL-induced transforming growth factor beta-1 (TGF-β1) production and hepatic collagen deposition, and the anti-fibrotic effects were accompanied by reductions in matrix-producing cells and Smad2/3. BDL rats showed increased hepatic NF-κB/AP-1 activities, inflammatory cell infiltration/accumulation, and cytokine production, and these signs of hepatic inflammation were ameliorated by rosmarinic acid. Mechanistic study revealed an inhibitory effect of rosmarinic acid on the axis of the high mobility group box-1 (HMGB1)/toll-like receptor-4 (TLR4) in BDL rats. Results of cultured hepatic stellate cells further showed the impacts of rosmarinic acid which attenuated TGF-β1-induced stellate cell mitogenic and fibrogenic activation. Our findings support the concept that rosmarinic acid could serve as a hepatoprotective agent, and dietary rosmarinic acid supplementation may be beneficial in terms of improving cholestasis-related liver injury via mechanisms involving resolution of oxidative burden and down-regulation of HMGB1/TLR4, NF-κB, AP-1, and TGF-β1/Smad signaling. Graphical abstract: Highlights: Bile duct ligation caused extrahepatic cholestasis in rodents. Rosmarinic acid showed improvement effects against cholestasis. Rosmarinic acid attenuated hepatic TGF-β1 signaling in BDL rats. Rosmarinic acid attenuated hepatic NF-κB/AP-1 activities in BDL rats. Rosmarinic acid attenuated hepatic HMGB1/TLR4 signaling in BDL rats.