title: Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance.
abstract: OBJECTIVE
  The global epidemic of metabolic syndrome and its complications demands rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin, has lipid-lowering properties and inhibits VLDL secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance in vivo.
  
  
  METHODS
  LDL receptor-null (Ldlr(-/-)) mice fed a high-fat (Western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant, and obese. Four groups of mice (standard diet, Western, and Western plus 1% or 3% wt/wt naringenin) were fed ad libitum for 4 weeks. VLDL production and parameters of insulin and glucose tolerance were determined.
  
  
  RESULTS
  We report that naringenin treatment of Ldlr(-/-) mice fed a Western diet corrected VLDL overproduction, ameliorated hepatic steatosis, and attenuated dyslipidemia without affecting caloric intake or fat absorption. Naringenin 1) increased hepatic fatty acid oxidation through a peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha/PPARalpha-mediated transcription program; 2) prevented sterol regulatory element-binding protein 1c-mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis; 4) reduced both VLDL-derived and endogenously synthesized fatty acids, preventing muscle triglyceride accumulation; and 5) improved overall insulin sensitivity and glucose tolerance.
  
  
  CONCLUSIONS
  Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome.
authors: Department of Vascular Biology, Robarts Research Institute, Ontario, Canada.
authors: Erin E
authors: EE
authors: Mulvihill
authors: Emma M
authors: EM
authors: Allister
authors: Brian G
authors: BG
authors: Sutherland
authors: Dawn E
authors: DE
authors: Telford
authors: Cynthia G
authors: CG
authors: Sawyez
authors: Jane Y
authors: JY
authors: Edwards
authors: Janet M
authors: JM
authors: Markle
authors: Robert A
authors: RA
authors: Hegele
authors: Murray W
authors: MW
authors: Huff
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology*; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism*; D001835:Body Weight; D004272:DNA, Mitochondrial / Q000235:genetics; D004041:Dietary Fats / Q000494:pharmacology; D050171:Dyslipidemias / Q000517:prevention & control*; D002149:Energy Intake; D004965:Estrogen Antagonists / Q000494:pharmacology*; D044950:Flavanones / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D000897:Anti-Ulcer Agents; D001055:Apolipoproteins B; D001786:Blood Glucose; D004272:DNA, Mitochondrial; D004041:Dietary Fats; D004965:Estrogen Antagonists; D044950:Flavanones; D007328:Insulin; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D014280:Triglycerides; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C005273:naringenin