Acyl-CoA metabolism and partitioning

Abstract

Long-chain fatty acyl-coenzyme As (CoAs) are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids such as triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs toward or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.

Keywords: acyl-CoA binding protein; acyl-CoA synthetase; bubblegum; cancer; fatty acid binding protein; fatty acid transport protein; metabolic syndrome; triacylglycerol; β-oxidation.

Figure 1

Metabolic fates of long-chain fatty acids. Long-chain fatty acids from exogenous or endogenous sources are activated to acyl-CoAs by one of 13 acyl-CoA synthetase isoforms. The free fatty acids are ligands for nuclear transcription factors and 20-carbon fatty acids can be converted to a variety of signaling eicosanoids. The acyl-CoAs are transcriptional ligands, substrates for β- and ω-oxidation, and can be incorporated into complex lipids or used to modify proteins. ACS, acyl-CoA synthetase; EET, epoxyeicosatrienoic acids; ER, endoplasmic reticulum; FA, fatty acid; HETE, hydroxyeicosatetraenoic acid; PPAR, peroxisome proliferator-activated receptor.

Figure 2

Acyl-CoA metabolism. The major initial enzymatic steps in the metabolism of long-chain acyl-CoAs include 13 independent thioesterases to hydrolyze acyl-CoAs, fatty acyl-CoA reductase, which converts the acyl-CoA to a fatty alcohol that will be incorporated into ether lipids, and ATs (acyl-CoA acyltransferases), which incorporate fatty acids into complex lipids and acylated proteins. In the major degradative pathways, CPT1 (carnitine palmitoyltransferase-1) converts acyl-CoAs to acylcarnitines that enter the mitochondria for β-oxidation, whereas very-long-chain acyl-CoAs begin to be oxidized in peroxisomes, releasing acetyl-CoAs, until they are chain-shortened to 8 carbons, which complete their oxidation in the mitochondria.