title: Caffeine protects against alcohol-induced liver fibrosis by dampening the cAMP/PKA/CREB pathway in rat hepatic stellate cells.
abstract: Alcoholic liver fibrosis (ALF) is characterized by hyperplasia of extracellular matrix under long-term alcohol stimulation. Hepatic stellate cell (HSC) activation plays an important role in promoting hepatic fibrogenesis. Caffeine, as the main active component of coffee and tea, was widely consumed in daily life. It was always a thought that caffeine can reduce the probability of suffering from liver diseases. In this study, we attempt to validate the hypothesis that caffeine inhibits activation of HSCs which were isolated from rat ALF model. The rats were gavaged by ethanol to establish ALF model and then treated with different concentrations of caffeine or colchicine. Serum was collected to measure the contents of serum alanine aminotransferase (ALT), aspartate transaminase (AST), hyaluronic acid (HA), laminin (LN), N-terminal peptide of type III procollagen (PIIINP) and type IV collagen (CIV). Then liver tissues were obtained for hematoxylin-eosin staining and Sirius-red staining. Others were treated through liver perfusion to isolate primary rat HSCs. Interestingly, we found that caffeine significantly decreased ALT, AST, HA, LN, PIIINP and CIV levels and reversed liver fibrosis in rat ALF models. Results of immunohistochemistry, real-time PCR and western blot indicated that caffeine could reduce fibrosis and inhibit cAMP/PKA/CREB signal pathway in HSC. Caffeine has a preventive effect on ALF. The mechanism may be interpreted that caffeine inhibits the cAMP/PKA/CREB signal pathway through adenosine A2A receptors in HSC.
authors.affiliation: School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China. Electronic address: leodd1992@126.com.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Fourth Affiliated Hospital of Anhui Medical University, Tun Xi Road, Hefei, Anhui Province, 230000, China.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Dai
authors.affiliation: The First Hospital of Anqing, Xiao Su Road, Anqing, Anhui Province, 246003, China.
authors.forename: Wanzhi
authors.initials: W
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China.
authors.forename: He
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China.
authors.forename: Han
authors.initials: H
authors.lastname: Zhao
authors.affiliation: School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: School of Pharmacy, Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China; Institute for Liver Disease of Anhui Medical University, Mei Shan Road, Hefei, Anhui Province, 230032, China. Electronic address: lxw31288@aliyun.com.
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Lv
mesh_terms: D000199:Actins / Q000378:metabolism; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002110:Caffeine / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D000431:Ethanol; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000097:blood; D007797:Laminin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D010446:Peptide Fragments / Q000097:blood; D011347:Procollagen / Q000097:blood; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000199:Actins; D000410:Alanine Transaminase; D001219:Aspartate Aminotransferases; D002110:Caffeine; D003094:Collagen; D000242:Cyclic AMP; D017362:Cyclic AMP Response Element-Binding Protein; D017868:Cyclic AMP-Dependent Protein Kinases; D000431:Ethanol; D006820:Hyaluronic Acid; D007797:Laminin; D010446:Peptide Fragments; D011347:Procollagen; C041876:procollagen Type III-N-terminal peptide; C498862:Acta2 protein, rat
keywords: Alcoholic liver fibrosis; CREB; Caffeine; Hepatic stellate cell; PKA; cAMP