title: Eugenol ameliorates hepatic steatosis and fibrosis by down-regulating SREBP1 gene expression via AMPK-mTOR-p70S6K signaling pathway.
abstract: Beneficial effect of eugenol on fatty liver was examined in hepatocytes and liver tissue of high fat diet (HFD)-fed C57BL/6J mice. To induce a fatty liver, palmitic acid or isolated hepatocytes from HFD-fed Sprague-Dawley (SD) rats were used in vitro studies, and C57BL/6J mice were fed HFD for 10 weeks. Lipid contents were markedly decreased when hepatocytes were treated with eugenol for up to 24 h. Gene expressions of sterol regulatory element binding protein 1 (SREBP1) and its target enzymes were suppressed but those of lipolysis-related proteins were increased. As a regulatory kinase for lipogenic transcriptional factors, the AMP-activated protein kinase (AMPK) signaling pathway was examined. Protein expressions of phosphorylated Ca(2+)-calmodulin dependent protein kinase kinase (CAMKK), AMPK and acetyl-CoA carboxylase (ACC) were significantly increased and those of phosphorylated mammalian target of rapamycin (mTOR) and p70S6K were suppressed when the hepatocytes were treated with eugenol at up to 100 µM. These effects were all reversed in the presence of specific inhibitors of CAMKK, AMPK or mTOR. In vivo studies, hepatic triglyceride (TG) levels and steatosis score were decreased by 45% and 72%, respectively, in eugenol-treated mice. Gene expressions of fibrosis marker protein such as α-smooth muscle actin (α-SMA), collagen type I (Col-I) and plasminogen activator inhibitor-1 (PAI-1) were also significantly reduced by 36%, 63% and 40% in eugenol-treated mice. In summary, eugenol may represent a potential intervention in populations at high risk for fatty liver.
authors.affiliation: Department of Pharmacology and Clinical Pharmacy, College of Pharmacy, Kyung Hee University.
authors.forename: Hee Kyung
authors.initials: HK
authors.lastname: Jo
authors.forename: Go Woon
authors.initials: GW
authors.lastname: Kim
authors.forename: Kyung Ju
authors.initials: KJ
authors.lastname: Jeong
authors.forename: Do Yeon
authors.initials: DY
authors.lastname: Kim
authors.forename: Sung Hyun
authors.initials: SH
authors.lastname: Chung
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000199:Actins / Q000235:genetics; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics; D015536:Down-Regulation; D005054:Eugenol / Q000494:pharmacology* / Q000627:therapeutic use; D005234:Fatty Liver / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D017395:Plasminogen Activator Inhibitor 1; D051780:Sterol Regulatory Element Binding Protein 1; C544013:alpha-smooth muscle actin, mouse; D005054:Eugenol; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase