title: Peroxisome proliferator-activated receptor γ down-regulation mediates the inhibitory effect of d-δ-tocotrienol on the differentiation of murine 3T3-F442A preadipocytes.
abstract: Tocotrienols accelerate the degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase that catalyzes the biosynthesis of mevalonate; the latter is essential for preadipocyte differentiation. Tocotrienols also down-regulate peroxisome proliferator-activated receptor γ (PPARγ), a key regulator of adipocyte differentiation. We hypothesized that mevalonate deprivation and PPARγ down-regulation mediate d-δ-tocotrienol-induced inhibition of adipocyte differentiation. The objectives of this study were to determine the effect of d-δ-tocotrienol on 3T3-F442A preadipocyte differentiation and the involvement of PPARγ and mevalonate. Murine 3T3-F442A preadipocytes were incubated with d-δ-tocotrienol (2.5-10 μmol/L) for 8 days. AdipoRed assay and Oil Red O staining showed that d-δ-tocotrienol dose-dependently reduced the intracellular triglyceride content. Concomitantly, d-δ-tocotrienol dose-dependently inhibited glucose uptake by 3T3-F442A cells and the expression of GLUT4, HMG CoA reductase, and p-Akt proteins. The effects of d-δ-tocotrienol on intracellular triglyceride content and glucose uptake were attenuated by rosiglitazone, an agonist of PPARγ, but not supplemental mevalonate (100 μmol/L). In contrast, mevalonate, but not rosiglitazone, reversed the effects of lovastatin, a competitive inhibitor of HMG CoA reductase shown to inhibit adipocyte differentiation via mevalonate deprivation. Trypan blue staining revealed no changes in cell viability after a 48-hour incubation of 3T3-F442A cells with d-δ-tocotrienol (0-80 μmol/L), suggesting that the adipogenesis-suppressive activity of d-δ-tocotrienol was independent of cytotoxicity. In conclusion, these findings demonstrate the antiadipogenic effect of d-δ-tocotrienol via PPARγ down-regulation.
authors.affiliation: Department of Nutrition and Food Sciences, Texas Woman's University, Denton, TX, USA. Electronic address: storabi@twu.edu.
authors.forename: Sheida
authors.initials: S
authors.lastname: Torabi
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: Hoda.Yeganehjoo@utsouthwestern.edu.
authors.forename: Hoda
authors.initials: H
authors.lastname: Yeganehjoo
authors.affiliation: Department of Pathology, Texas Tech University Health Sciences Center, Lubbock, TX, USA. Electronic address: leslie.shen@ttuhsc.edu.
authors.forename: Chwan-Li
authors.initials: CL
authors.lastname: Shen
authors.affiliation: Department of Nutrition, Byrdine F. Lewis School of Nursing and Health Professions, Georgia State University, Atlanta, GA, USA; Center for Obesity Reversal, Georgia State University, Atlanta, GA, USA. Electronic address: hmo@gsu.edu.
authors.forename: Huanbiao
authors.initials: H
authors.lastname: Mo
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects* / Q000502:physiology; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D051275:Glucose Transporter Type 4; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone; D014810:Vitamin E; C082097:tocotrienol, delta; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D008798:Mevalonic Acid
keywords: Adipocyte; Lovastatin; Mevalonate; PPARγ; Tocotrienol