Materials == Acetonitrile (EMD Chemicals, Gibbstown, NJ); acetic acid, chloroform, KH2PO4, HCl, hexane, KOH, H2SO4(J
Materials == Acetonitrile (EMD Chemicals, Gibbstown, NJ); acetic acid, chloroform, KH2PO4, HCl, hexane, KOH, H2SO4(J.T. DNL and induce FAO, but will also attenuate the synthesis of very long chain saturated, mono- and polyunsaturated fatty acids. Keywords:acetyl CoA carboxylase, soraphen A, de novo lipogenesis, fatty acid elongation, fatty acid desaturation, fatty acid oxidation == 1. Introduction == Global and tissue specific ablation of acetyl CoA carboxylase-1 [ACC1] [1,2], ACC2 [3], fatty acid synthase [FASN] [4] or stearoyl CoA desaturase-1 [SCD1] [5,6] significantly impacts lipid synthesis, storage and oxidation and affects the onset and progression of obesity and diabetes. Such studies have prompted an interest in developing pharmacological approaches to control lipid synthesis and storage in an effort to combat obesity, diabetes, metabolic syndrome and cancer [711]. ACC has emerged as one target for such control because of its role in malonyl CoA synthesis, a substrate forde novolipogenesis (DNL) and an allosteric inhibitor of carnitine palmitoyl transferase-1 (CPT1) and mitochondrial fatty acid oxidation [FAO] [1215]. While both ACC1 and ACC2 isoforms generate BRL-15572 malonyl CoA, their subcellular location leads to different effects on lipid metabolism. Cytosolic ACC1 generates malonyl CoA for DNL, while mitochondrial ACC2 generates malonyl CoA to inhibit CPT1 and FAO [14]. Although there has been considerable interest in ACC as a therapeutic target to attenuate fatty acid synthesis and enhance fatty acid oxidation [7,13,16,17], little attention has been given to BRL-15572 the role ACC plays in long chain saturated (SFA), mono-(MUFA) and polyunsaturated (PUFA) fatty acid synthesis. Malonyl CoA is usually a substrate for microsomal fatty acid elongation [18]. Fatty acid elongation & desaturation is critical for generating BRL-15572 the diverse array of SFA, MUFA and PUFA found in cells [1921]. In addition to malonyl CoA, microsomal fatty acid elongation requires other substrates (NADPH and fatty acyl CoAs) and four enzymes to catalyze the 2-carbon elongation of fatty acids derived from the diet or DNL. These enzymes include 3-keto acyl CoA synthase, 3-keto acyl CoA reductase, 3-hydroxy acyl CoA dehydratase and trans 2,3-enoyl CoA reductase [1820]. Specificity for fatty acyl CoA substrates and the rate of fatty acid elongation is determined by the 1ststep in the pathway, i.e., the activity of the condensing enzyme, 3-keto acyl CoA synthase, and not the reductases or dehydratase [18,22,23]. As such, 3-keto acyl CoA synthase (also known as Elovl, elongation of long chain fatty acids) plays the key regulatory role in determining the type and amount of elongated fatty acids found in cells. Seven fatty acid elongases (Elovl17) have been described in rodent and human genomes. Many fatty acid elongases function together with fatty acid desaturases to generate very long chain MUFA and PUFA. Elongases and desaturases in these pathways are coordinately regulated [24,25]. For example, SCD1 and fatty acid elongase-6 (Elovl6) are induced by insulin, glucose and liver X Rabbit Polyclonal to NOM1 receptor (LXR) & peroxisome proliferator activated receptor- (PPAR) agonist. SCD1 and Elovl6 play a major role in MUFA synthesis. The global ablation of SCD1 or Elovl6 significantly impacts fatty acid and triglyceride synthesis as well as the onset of diet-induced fatty liver, obesity & insulin resistance [2628]. PPAR agonist induce Elovl5, FADS1 and FADS2 leading to the stimulation of PUFA synthesis [24,29]. Global ablation of Elovl5 lowers PUFA synthesis and relieves PUFA suppression of SREBP1, a key transcription factor controlling fatty acid synthesis [30]. In contrast, elevation of hepatic Elovl5 activity lowers hepatic & plasma triglyceride content [29]. These studies establish that changes in fatty acid elongation impacts cellular fatty acid composition; some of these changes are linked to chronic metabolic disease. Despite the numerous studies on ACC1 BRL-15572 [1,2] and ACC2 [3] function and the potential role of ACC as a therapeutic target for metabolic and neoplastic disease [7,13,16,17], no studies have assessed the effect of.