title: β-Caryophyllene attenuates palmitate-induced lipid accumulation through AMPK signaling by activating CB2 receptor in human HepG2 hepatocytes.
abstract: Nonalcoholic fatty liver disease is currently the most common chronic liver disease worldwide, characterized by excessive hepatic lipid accumulation without significant ethanol consumption. We have performed a screening for medicinal foods that inhibit hepatocytic lipid accumulation through activation of AMP-activated protein kinase (AMPK), which is a critical regulator of the hepatic lipid metabolism.
  
  
  
  We found that clove (Syzygium aromaticum), which is commonly used as a spice, markedly inhibits palmitate-inducible lipid accumulation in human HepG2 hepatocytes. Analyses of the clove extracts found that β-caryophyllene, an orally-active cannabinoid, is the principal suppressor of the lipid accumulation, and stimulates the phosphorylation of AMPK and acetyl-CoA carboxylase 1 (ACC1). Our data also showed that β-caryophyllene prevents the translocation of sterol regulatory element-binding protein-1c (SREBP-1c) into the nucleus and forkhead box protein O1 (FoxO1) into the cytoplasm through AMPK signaling, and consequently, induces a significant downregulation of fatty acid synthase (FAS) and upregulation of adipose triglyceride lipase, respectively. Moreover, we demonstrated that the β-caryophyllene-induced activation of AMPK could be mediated by the cannabinoid type 2 receptor-dependent Ca2+signaling pathway.
  
  
  
  Our results suggest that β-caryophyllene has the potential efficacy in preventing and ameliorating nonalcoholic fatty liver disease and its associated metabolic disorders.
authors.affiliation: Department of Biological Chemistry, Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kamikubo
authors.affiliation: Department of Biological Chemistry, Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kai
authors.affiliation: Division 2, DHC Corporation Laboratories, Hamada, Mihama-ku, Chiba, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Tsuji-Naito
authors.affiliation: Department of Biological Chemistry, Division of Applied Life Sciences, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Japan. akagawa@biochem.osakafu-u.ac.jp.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Akagawa
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D000071161:Forkhead Box Protein O1 / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D065626:Non-alcoholic Fatty Liver Disease / Q000517:prevention & control; D010168:Palmitates / Q000009:adverse effects / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*; D012717:Sesquiterpenes / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D027842:Syzygium / Q000737:chemistry
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D010168:Palmitates; D010936:Plant Extracts; D000081223:Polycyclic Sesquiterpenes; D043885:Receptor, Cannabinoid, CB2; D012717:Sesquiterpenes; D051780:Sterol Regulatory Element Binding Protein 1; C024714:caryophyllene; D055372:AMP-Activated Protein Kinases; D002118:Calcium
keywords: AMP-activated protein kinase (AMPK); Cannabinoid type 2 (CB2) receptor; Clove (Syzygium aromaticum); NAFLD; β-Caryophyllene