Deactivating Fatty Acids: Acyl-CoA Thioesterase-Mediated Control of Lipid Metabolism

Abstract

The cellular uptake of free fatty acids (FFA) is followed by esterification to coenzyme A (CoA), generating fatty acyl-CoAs that are substrates for oxidation or incorporation into complex lipids. Acyl-CoA thioesterases (ACOTs) constitute a family of enzymes that hydrolyze fatty acyl-CoAs to form FFA and CoA. Although biochemically and biophysically well characterized, the metabolic functions of these enzymes remain incompletely understood. Existing evidence suggests regulatory roles in controlling rates of peroxisomal and mitochondrial fatty acyl-CoA oxidation, as well as in the subcellular trafficking of fatty acids. Emerging data implicate ACOTs in the pathogenesis of metabolic diseases, suggesting that better understanding their pathobiology could reveal unique targets in the management of obesity, diabetes, and nonalcoholic fatty liver disease.

Keywords: energy homeostasis; fatty acyl-CoA; free fatty acid; mitochondria; peroxisomes.

Figure 1. Relationships between the ACOT and START domain protein families

The ACOT and START-domain protein families are divided into sub-groups. ACOTs are each divided into Type I and Type II ACOTs based on structure, with Type I enzymes containing an α/β Hydrolase catalytic domain and Type II enzymes containing single or tandem HotDog domains. START domain proteins are sub-grouped as multidomain and minimal, which denotes the presence of the START domain as the only domain. ACOT11/THEM1 (StARD14) and ACOT12 (StARD15) are shared in ACOT and START protein families because they each harbor both a tandem HotDog domain and a START domain. The dashed arrow indicates an additional connection between the ACOT and START domain protein families: ACOT13/THEM2 and StARD2/PC-TP are interacting proteins. Abbreviations: ACOT, acyl-CoA thioesterase; M, MLN64 N-terminal domain of StARD3; Mt mitochondrial targeting signal of StARD1; ND, N-terminal domain; PH, pleckstrin homology; RHO, Rho GTPase activating protein; SAM, sterile alpha motif; START, steroidogenic acute regulatory protein-related lipid transfer

Figure 2. ACOT11/THEM1 and ACOT13/THEM2 function in brown adipose tissue and liver

(Top panel) THEM1 is highly expressed in brown adipose tissue and is upregulated by cold exposure. Upon adrenergic stimulus that occurs in response to cold exposure, lipolysis of lipid droplets leads to the release of fatty acids that are directed towards mitochondria for β-oxidation in order to support thermogenesis. THEM1 functions to reduce energy expenditure by limiting the oxidation of fatty acids derived from the lipolysis of lipid droplets. Adopted with permission from reference [54]. (Bottom panel) THEM2 is enriched in liver together with its interacting partner PC-TP. During fasting, THEM2 directs fatty acids towards mitochondria for β-oxidation, where the increased TCA cycle flux can support gluconeogenesis. In the setting of overnutrition, THEM2 may also promote an increase in flux of fatty acids towards glycerolipid synthesis, which can lead to the production of lipids that suppress insulin signaling. Adopted with permission from reference [68]. Abbreviations: ACSL1, Long chain acyl-CoA synthetase 1; ACSLx, Acyl-CoA synthetase that is as yet unidentified; CPT, Carnitine palmitoyl transferase; ER, endoplasmic reticulum, ETC, electronic transport chain; GPAT1, glycerol-3-phosphate acyltransferase 1; LD, lipid droplet; LPA, lysophosphatic acid; PC, phosphatidylcholine; TAG, triacylglycerol; TCA; tricarboxylic acid cycle; UCP, uncoupling protein; VLDL, very low density lipoprotein.

Text box figure. Role of ACOTs in peroxisomal lipid metabolism

Acyl-CoA esters enter peroxisomes via different dimers of the ATP-binding cassette D (ABCD1-3) transporters located in the membrane. Imported acyl-CoA esters (including CoA esters of bile acid intermediates and various very long- and long-chain acyl-CoAs) are shorted by β-oxidation to achieve acyl chain-lengths that are suitable substrates for the various ACOTs contained within the organelle. Not shown are that peroxisomes also contain short- and medium-chain acylcarnitine transferases that can convert acyl-CoAs to the corresponding carnitine esters, which are transported out of peroxisomes. Adopted with permission from reference [5]. Abbreviations: ABCD; ATP-binding cassette D transporter; BA, bile acid; BA(I), bile acid intemediate; BAAT, bile acid-CoA:amino acid N-acyltransferase; FFA, free fatty acid; Gly, glycine; LCA, long chain acyl; LCDCA, long chain dicarboxylic acyl; LFA, long chain fatty acyl; MCA, medium chain acyl; MFA, medium chain fatty acyl; Tau, taurine; SCDCA, short chain dicarboxylic acyl; SDCFA, short chain dicarboxylic fatty acid;VLCA, very long chain acyl.