title: Inhibition of acetyl-CoA carboxylases by soraphen A prevents lipid accumulation and adipocyte differentiation in 3T3-L1 cells.
abstract: Acetyl-CoA carboxylases (ACC) 1 and 2 catalyze the carboxylation of acetyl-CoA to malonyl-CoA and depend on biotin as a coenzyme. ACC1 localizes in the cytoplasm and produces malonyl-CoA for fatty acid (FA) synthesis. ACC2 localizes in the outer mitochondrial membrane and produces malonyl-CoA that inhibits FA import into mitochondria for subsequent oxidation. We hypothesized that ACCs are checkpoints in adipocyte differentiation and tested this hypothesis using the ACC1 and ACC2 inhibitor soraphen A (SA) in murine 3T3-L1 preadipocytes. When 3T3-L1 cells were treated with 100nM SA for 8 days after induction of differentiation, the expression of PPARγ mRNA and FABP4 mRNA decreased by 40% and 50%, respectively, compared with solvent controls; the decrease in gene expression was accompanied by a decrease in FABP4 protein expression and associated with a decrease in lipid droplet accumulation. The rate of FA oxidation was 300% greater in SA-treated cells compared with vehicle controls. Treatment with exogenous palmitate restored PPARγ and FABP4 mRNA expression and FABP4 protein expression in SA-treated cells. In contrast, SA did not alter lipid accumulation if treatment was initiated on day eight after induction of differentiation. We conclude that loss of ACC1-dependent FA synthesis and loss of ACC2-dependent inhibition of FA oxidation prevent lipid accumulation in adipocytes and inhibit early stages of adipocyte differentiation.
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Leverton Hall, Lincoln, NE 68583-0806, USA.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Cordonier
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Leverton Hall, Lincoln, NE 68583-0806, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Jarecke
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Leverton Hall, Lincoln, NE 68583-0806, USA.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Hollinger
authors.affiliation: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Leverton Hall, Lincoln, NE 68583-0806, USA. Electronic address: jzempleni2@unl.edu.
authors.forename: Janos
authors.initials: J
authors.lastname: Zempleni
mesh_terms: D041721:3T3-L1 Cells; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D007328:Insulin / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects*; D018942:Macrolides / Q000494:pharmacology*; D051379:Mice; D010084:Oxidation-Reduction / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics; D019308:Palmitic Acid / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D007328:Insulin; D018942:Macrolides; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C086151:soraphen A; D019308:Palmitic Acid; D000103:Acetyl-CoA Carboxylase
keywords: Acetyl-CoA carboxylase; Adipogenesis; Lipid metabolism; Peroxisome-proliferator-activated receptor gamma; Soraphen A