title: Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance.
abstract: OBJECTIVE
  Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.
  
  
  METHODS
  Lipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor-deficient mice (Ldlr(-/-)) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.
  
  
  RESULTS
  In HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal-related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr(-/-) mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator-activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.
  
  
  CONCLUSIONS
  Nobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.
authors.affiliation: Vascular Biology, Robarts Research Institute, London, Ontario, Canada.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Mulvihill
authors.forename: Julia M
authors.initials: JM
authors.lastname: Assini
authors.forename: Justin K
authors.initials: JK
authors.lastname: Lee
authors.forename: Emma M
authors.initials: EM
authors.lastname: Allister
authors.forename: Brian G
authors.initials: BG
authors.lastname: Sutherland
authors.forename: Julie B
authors.initials: JB
authors.lastname: Koppes
authors.forename: Cynthia G
authors.initials: CG
authors.lastname: Sawyez
authors.forename: Jane Y
authors.initials: JY
authors.lastname: Edwards
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Telford
authors.forename: Alexandre
authors.initials: A
authors.lastname: Charbonneau
authors.forename: Philippe
authors.initials: P
authors.lastname: St-Pierre
authors.forename: André
authors.initials: A
authors.lastname: Marette
authors.forename: Murray W
authors.initials: MW
authors.lastname: Huff
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D004032:Diet / Q000009:adverse effects*; D050171:Dyslipidemias / Q000188:drug therapy* / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047309:Flavones / Q000627:therapeutic use*; D056945:Hep G2 Cells; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011972:Receptor, Insulin / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D047309:Flavones; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008079:Lipoproteins, VLDL; D009570:Nitriles; D014280:Triglycerides; C113580:U 0126; C030106:very low density lipoprotein triglyceride; C008661:nobiletin; C482128:MAP2K2 protein, human; D011972:Receptor, Insulin; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human