Eugenol Ameliorates Hepatic Steatosis and Fibrosis by Down-Regulating SREBP1 Gene Expression via AMPK-mTOR-p70S6K Signaling Pathway

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 we...

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Published in:Biological & pharmaceutical bulletin 2014/08/01, Vol.37(8), pp.1341-1351
Main Authors: Jo, Hee Kyung, Kim, Go Woon, Jeong, Kyung Ju, Kim, Do Yeon, Chung, Sung Hyun
Format: Article
Language:eng ; jpn
Subjects:
Acetyl-CoA Carboxylase - metabolism
Actins - genetics
AMP-activated protein kinase
AMP-Activated Protein Kinases - metabolism
Animals
Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism
Cells, Cultured
Collagen Type I - genetics
Down-Regulation
eugenol
Eugenol - pharmacology
Eugenol - therapeutic use
fatty liver
Fatty Liver - drug therapy
Fatty Liver - genetics
Fatty Liver - metabolism
Fatty Liver - pathology
Fibrosis
Hep G2 Cells
Hepatocytes - drug effects
Hepatocytes - metabolism
Humans
Liver - pathology
Male
Mice, Inbred C57BL
Plasminogen Activator Inhibitor 1 - genetics
Rats, Sprague-Dawley
Ribosomal Protein S6 Kinases, 70-kDa - metabolism
sterol regulatory element binding protein
Sterol Regulatory Element Binding Protein 1 - genetics
TOR Serine-Threonine Kinases - metabolism
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Summary: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 Ca2+-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.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.b14-00281