title: Modulation by geraniol of gene expression involved in lipid metabolism leading to a reduction of serum-cholesterol and triglyceride levels.
abstract: BACKGROUND
  Geraniol (G) is a natural isoprenoid present in the essential oils of several aromatic plants, with various biochemical and pharmacologic properties. Nevertheless, the mechanisms of action of G on cellular metabolism are largely unknown.
  
  
  OBJECTIVE
  We propose that G could be a potential agent for the treatment of hyperlipidemia that could contribute to the prevention of cardiovascular disease. The aim of the present study was to advance our understanding of its mechanism of action on cholesterol and TG metabolism.
  
  
  METHODS
  NIH mice received supplemented diets containing 25, 50, and 75 mmol G/kg chow. After a 3-week treatment, serum total-cholesterol and triglyceride levels were measured by commercial kits and lipid biosynthesis determined by the [(14)C] acetate incorporated into fatty acids plus nonsaponifiable and total hepatic lipids of the mice. The activity of the mRNA encoding HMGCR-the rate-limiting step in cholesterol biosynthesis-along with the enzyme levels and catalysis were assessed by real-time RT-PCR, Western blotting, and HMG-CoA-conversion assays, respectively. In-silico analysis of several genes involved in lipid metabolism and regulated by G in cultured cells was also performed. Finally, the mRNA levels encoded by the genes for the low-density-lipoprotein receptor (LDLR), the sterol-regulatory-element-binding transcription factor (SREBF2), the very-low-density-lipoprotein receptor (VLDLR), and the acetyl-CoA carboxylase (ACACA) were determined by real-time RT-PCR.
  
  
  RESULTS
  Plasma total-cholesterol and triglyceride levels plus hepatic fatty-acid, total-lipid, and nonsaponifiable-lipid biosynthesis were significantly reduced by feeding with G. Even though an up-regulation of the mRNA encoding HMGCR occurred in the G treated mouse livers, the protein levels and specific activity of the enzyme were both inhibited. G also enhanced the mRNAs encoding the LDL and VLDL receptors and reduced ACACA mRNA, without altering the transcription of the mRNA encoding the SREBF2.
  
  
  CONCLUSIONS
  The following mechanisms may have mediated the decrease in plasma lipids levels in mice: a down-regulation of hepatocyte-cholesterol synthesis occurred as a result of decreased HMGCR protein levels and catalytic activity; the levels of LDLR mRNA became elevated, thus suggesting an increase in the uptake of serum LDL, especially by the liver; and TG synthesis became reduced very likely because of a decrease in fatty-acid synthesis.
authors.affiliation: INIBIOLP (UNLP-CONICET CCT La Plata), Facultad de Ciencias Médicas, Calles 60 y 120, La Plata, Argentina.
authors.forename: Marianela
authors.initials: M
authors.lastname: Galle
authors.affiliation: INIBIOLP (UNLP-CONICET CCT La Plata), Facultad de Ciencias Médicas, Calles 60 y 120, La Plata, Argentina.
authors.forename: Boris Rodenak
authors.initials: BR
authors.lastname: Kladniew
authors.affiliation: INIBIOLP (UNLP-CONICET CCT La Plata), Facultad de Ciencias Médicas, Calles 60 y 120, La Plata, Argentina.
authors.forename: María Agustina
authors.initials: MA
authors.lastname: Castro
authors.affiliation: INIBIOLP (UNLP-CONICET CCT La Plata), Facultad de Ciencias Médicas, Calles 60 y 120, La Plata, Argentina.
authors.forename: Sandra Montero
authors.initials: SM
authors.lastname: Villegas
authors.affiliation: CINIBA (UNLP-CONICET CCT La Plata), Facultad de Ciencias MéG dicas, Calles 60 y 120, La Plata, Argentina.
authors.forename: Ezequiel
authors.initials: E
authors.lastname: Lacunza
authors.affiliation: INIBIOLP (UNLP-CONICET CCT La Plata), Facultad de Ciencias Médicas, Calles 60 y 120, La Plata, Argentina.
authors.forename: Mónica
authors.initials: M
authors.lastname: Polo
authors.affiliation: INIBIOLP (UNLP-CONICET CCT La Plata), Facultad de Ciencias Médicas, Calles 60 y 120, La Plata, Argentina.
authors.forename: Margarita García
authors.initials: MG
authors.lastname: de Bravo
authors.affiliation: INIBIOLP (UNLP-CONICET CCT La Plata), Facultad de Ciencias Médicas, Calles 60 y 120, La Plata, Argentina. Electronic address: rcrespo@med.unlp.edu.ar.
authors.forename: Rosana
authors.initials: R
authors.lastname: Crespo
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000080462:Acyclic Monoterpenes; D000818:Animals; D002784:Cholesterol / Q000097:blood*; D005260:Female; D015870:Gene Expression; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006949:Hyperlipidemias; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology; D012333:RNA, Messenger / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood*
chemical_list: D000080462:Acyclic Monoterpenes; D012333:RNA, Messenger; D011973:Receptors, LDL; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D013729:Terpenes; D014280:Triglycerides; C036053:VLDL receptor; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D000103:Acetyl-CoA Carboxylase; C007836:geraniol
keywords: ACACA; Geraniol; HMGCR; Hypolipemia; Lipogenesis