title: Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway.
abstract: BACKGROUND
  Carnosic acid (CA), found in rosemary, has been reported to have antioxidant and anti-adipogenic properties. We recently demonstrated that CA protects against steatosis in ob/ob mice. In the present report, we investigated the molecular mechanism by which CA inhibits lipids accumulation both in vivo and in vitro.
  
  
  METHODS
  In the in vivo study, ob/ob mice were fed a standard chow diet with or without CA for 5 weeks, then their hepatocyte lipid accumulation was determined. The serum concentrations of cytokines, the levels of lipid regulatory mediators, and the hepatic metabolic and signaling molecules were also evaluated. In the in vitro study, HepG2 cells were used to further clarify the effects of CA on cellular lipid accumulation and to confirm the signaling pathways involved in these effects.
  
  
  RESULTS
  CA significantly reduced hepatocyte lipid accumulation. This effect was associated with repressed levels of hepatic PPARγ, reduced expression of inflammatory cytokines such as IL-1β, IL-12, IL-17, IFN-γ, MCP-1, and MIP-1β, and increased ATP, acetyl CoA, NAD(P)(+), and NAD(P)H. Other signaling molecules, such as EGFR, MAPK, AMPK, and ACC, which regulate lipid metabolism, were activated in mice fed the CA diet. CA inhibited palmitate-induced cellular lipid accumulation and stimulated the phosphorylation of both EGFR and MAPK. Pretreatment with either the EGFR inhibitor AG1478 or the MEK-specific inhibitor U0126 abolished the effects of CA on cellular lipid accumulation and decreased both the protein expression and activity of PPARγ.
  
  
  CONCLUSIONS
  EGFR/MAPK signaling plays an important role in the inhibitory effect of CA on hepatocyte lipid accumulation.
authors.affiliation: Department of Gastroenterology and Hepatology, Iwate Medical University, Morioka, Iwate, Japan.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takikawa
authors.forename: Takahito
authors.initials: T
authors.lastname: Tabuchi
authors.forename: Takumi
authors.initials: T
authors.lastname: Satoh
authors.forename: Kunio
authors.initials: K
authors.lastname: Kosaka
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Suzuki
mesh_terms: D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020738:Leptin / Q000172:deficiency; D050356:Lipid Metabolism / Q000187:drug effects*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008820:Mice, Obese; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010936:Plant Extracts / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D045784:Abietanes; D000975:Antioxidants; D016207:Cytokines; D020738:Leptin; D047495:PPAR gamma; D010936:Plant Extracts; D066246:ErbB Receptors; C018381:salvin