Physiological Consequences of Compartmentalized Acyl-CoA Metabolism

Abstract

Meeting the complex physiological demands of mammalian life requires strict control of the metabolism of long-chain fatty acyl-CoAs because of the multiplicity of their cellular functions. Acyl-CoAs are substrates for energy production; stored within lipid droplets as triacylglycerol, cholesterol esters, and retinol esters; esterified to form membrane phospholipids; or used to activate transcriptional and signaling pathways. Indirect evidence suggests that acyl-CoAs do not wander freely within cells, but instead, are channeled into specific pathways. In this review, we will discuss the evidence for acyl-CoA compartmentalization, highlight the key modes of acyl-CoA regulation, and diagram potential mechanisms for controlling acyl-CoA partitioning.

Keywords: acyl-CoA; acyltransferase; fatty acid metabolism; fatty acid oxidation; phospholipid; thermogenesis; thioesterase; triacylglycerol.

FIGURE 1.

Metabolic reactions of acyl-CoAs. Long-chain FAs are synthesized de novo from acetate or enter cells from the plasma. They are converted to acyl-CoAs by ACSL and ACSVL. The reaction is reversed by acyl-CoA thioesterases (ACOT). Acyl-CoAs can be elongated and desaturated, converted to acylcarnitines, and metabolized to CO₂ via mitochondrial and peroxisomal enzymes, esterified to glycerol-3-phosphate to form lysophosphatidic acid (LPA), phosphatidic acid (PA), and TAG, and esterified to monoacylglycerol (MAG) to form diacylglycerol (DAG). Both phosphatidic acid and diacylglycerol are precursors for all the glycerophospholipids. Acyl-CoAs are also esterified to retinol and cholesterol, acylated to proteins, and incorporated into ceramide to form sphingolipids. Lipolysis of these products releases fatty acids back into cellular pools. Triacylglycerol, cholesterol esters, and retinol esters are stored in lipid droplets within cells or secreted from specialized cells as lipoproteins or milk constituents. NEFA, non-esterified fatty acid.

FIGURE 2.

A hypothetical assembly of proteins, substrates, and products that are critical for thermogenesis in brown adipocytes. Mice are unable to maintain a normal body temperature if they lack ATGL, FABP3, FATP1, and ACSL1 or are heterozygotes for CPT1. 1) ATGL hydrolyzes FA from TAG in lipid droplets. 2) FABP3 binds these released FAs and transports them to FATP1 and ACSL1, which convert them to acyl-CoAs (A-CoA). 3) These acyl-CoAs are substrates for CPT1, which converts them to acylcarnitines (AC) that enter the mitochondrial matrix and are metabolized by β-oxidation to produce heat. 4) Thioesterase superfamily member-2 (Them2) and its partner phosphatidylcholine transfer protein (PC-TP) improve the thermogenic process by converting acyl-CoAs, perhaps those formed in other locations, back to fatty acids that can be reactivated by FATP1 and ACSL1 located at the mitochondrial membrane. TCA, tricarboxylic acid cycle.