title: Soraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation.
abstract: Acetyl CoA carboxylase (ACC1 and ACC2) generates malonyl CoA, a substrate for de novo lipogenesis (DNL) and an inhibitor of mitochondrial fatty acid β-oxidation (FAO). Malonyl CoA is also a substrate for microsomal fatty acid elongation, an important pathway for saturated (SFA), mono- (MUFA) and polyunsaturated fatty acid (PUFA) synthesis. Despite the interest in ACC as a target for obesity and cancer therapy, little attention has been given to the role ACC plays in long chain fatty acid synthesis. This report examines the effect of pharmacological inhibition of ACC on DNL and palmitate (16:0) and linoleate (18:2, n-6) metabolism in HepG2 and LnCap cells. The ACC inhibitor, soraphen A, lowers cellular malonyl CoA, attenuates DNL and the formation of fatty acid elongation products derived from exogenous fatty acids, i.e., 16:0 and 18:2, n-6; IC(50)∼5nM. Elevated expression of fatty acid elongases (Elovl5, Elovl6) or desaturases (FADS1, FADS2) failed to override the soraphen A effect on SFA, MUFA or PUFA synthesis. Inhibition of fatty acid elongation leads to the accumulation of 16- and 18-carbon unsaturated fatty acids derived from 16:0 and 18:2, n-6, respectively. Pharmacological inhibition of ACC activity will not only attenuate DNL and induce FAO, but will also attenuate the synthesis of very long chain saturated, mono- and polyunsaturated fatty acids.
authors.affiliation: Department of Nutrition and Exercise Sciences, The Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, United States. Donald.Jump@oregonstate.edu
authors.forename: Donald B
authors.initials: DB
authors.lastname: Jump
authors.forename: Moises
authors.initials: M
authors.lastname: Torres-Gonzalez
authors.forename: L Karl
authors.initials: LK
authors.lastname: Olson
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000123:Acetyltransferases / Q000096:biosynthesis; D045744:Cell Line, Tumor; D000090943:Delta-5 Fatty Acid Desaturase; D044943:Fatty Acid Desaturases / Q000378:metabolism; D000081031:Fatty Acid Elongases; D005227:Fatty Acids / Q000096:biosynthesis*; D006801:Humans; D019787:Linoleic Acid / Q000378:metabolism; D050155:Lipogenesis / Q000187:drug effects; D018942:Macrolides / Q000494:pharmacology*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; C000630954:ELOVL5 protein, human; C000630955:ELOVL6 protein, human; D005227:Fatty Acids; D018942:Macrolides; C086151:soraphen A; D019308:Palmitic Acid; D019787:Linoleic Acid; D044943:Fatty Acid Desaturases; C000716847:FADS1 protein, human; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D000103:Acetyl-CoA Carboxylase