TitleSoraphen A, an inhibitor of acetyl CoA carboxylase activity, interferes with fatty acid elongation.
Publication TypeJournal Article
Year of Publication2011
AuthorsJump DB, Torres-Gonzalez M, L Olson K
JournalBiochem Pharmacol
Volume81
Issue5
Pagination649-60
Date Published2011 Mar 01
ISSN1873-2968
KeywordsAcetyl-CoA Carboxylase, Acetyltransferases, Cell Line, Tumor, Fatty Acid Desaturases, Fatty Acids, Humans, Linoleic Acid, Lipogenesis, Macrolides, Oxidation-Reduction, Palmitic Acid
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.

DOI10.1016/j.bcp.2010.12.014
Alternate JournalBiochem. Pharmacol.
PubMed ID21184748
PubMed Central IDPMC3031740
Grant ListR43 DK068962 / DK / NIDDK NIH HHS / United States
R44 DK068962 / DK / NIDDK NIH HHS / United States
R01 DK043220 / DK / NIDDK NIH HHS / United States
R01 DK043220-17 / DK / NIDDK NIH HHS / United States
DK43220 / DK / NIDDK NIH HHS / United States
DK068962 / DK / NIDDK NIH HHS / United States