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 acylCoA partitioning.Two prevailing views of metabolic pathways within the cytosol are a) as sequential steps within a largely empty space with substrates and products traveling from one enzyme to the next, and b), as embedded within a dense network of proteins and metabolites, all jockeying for position. In contrast to these two views, it is likely that synthetic and degradative pathways are composed of enzymes and their regulators in highly organized multi-enzyme assemblies designed to enhance efficiency and regulate steady-state flux (1). Proteins within these assemblies might interact via their transmembrane and extra-membrane domains or be tethered to scaffolds, in a manner that is regulated by allosteric effectors and post-translational modifications (2, 3). Such interactions may be transient, as occurs with the enzymes that comprise purinosomes (4), or they may be semi-permanent as occurs within glycogen granules that contain enzymes that synthesize and degrade glycogen, and their regulatory kinases and phosphatases (5, 6). Assemblies of proteins are advantageous because even without a physical tunnel, they can increase reaction rates by enhancing local substrate concentrations, restricting intermediates from entering competing reactions, and stabilizing chemically unstable intermediates.Because the dysregulation of metabolic homeostasis has been implicated in a multitude of human diseases, acyl-CoA metabolism represents a critical node for understanding whole-body pathophysiology. Apart from eicosanoid synthesis, the first step in the metabolism of long-chain fatty acids (FAs) 2 is their thioesterification. The resulting acyl-CoA is then metabolized by one of six major enzyme families: elongases and desaturases (7), dehydrogenases (8, 9), acyl-CoA thioesterases (10, 11), carnitine palmitoyltransferases (CPT) (12), and lipid and protein acyltransferases (13) (Fig. 1). These competing pathways, often present within a single subcellular compartment and coupled with the highly specialized metabolism of individual cells and tissues, suggest a level of organization extending beyond enzymatic function. In this review, we will use a physiological lens to focus on longchain mammalian fatty acyl-CoAs and the evidence for compartmentalized acyl-CoA metabolism.

Acyl CoA synthetase-1 links facilitated long chain fatty acid uptake to intracellular metabolic trafficking differently in hearts of male versus female mice

“…The FFA concentration gradient across the membrane increases through rapid conversion of intracellular FFA to fatty acyl CoA. Fatty acid metabolic trapping was previously only hypothesized in cells based on increased content of radiolabeled or fluorescent fatty acids in cells [7,9-11,13,16]. Here, with an in vivo , model we show accelerated trapping of fatty acids by ACSL1 resulted in greater LCFA uptake rates and FFA conversion to acyl CoA in ACSL1 overexpressing hearts (Figure 3A).…”

“…ACSL1 has been localized to the mitochondria outer membrane and based on ACSL1 knockout studies it might be expected that ACSL1 channels lipids into the mitochondria for beta-oxidation [10,13,15,16,33,46-48]. Studies of ACSL1 knockout mice, whole body or specific to heart muscle, skeletal muscle, liver, and adipose, revealed reduced LCFA oxidation [15,46-48].…”

“…Despite the importance of ACSL1 in initiating intracellular lipid usage, the impact of ACSL1 on active fatty acid uptake rates and the consequences of altered uptake on cellular lipid utilization in the heart are not understood. Potentially, ACSL1 vectorial acylation can affect uptake rates by esterification of a LCFA to a coenzyme A thioester forming a fatty acyl CoA, which traps the fatty acid in the cell, reduces intracellular free fatty acid (FFA) concentration, and increases the driving force for FFA transport across the plasma membrane [7,16]. …”

Carnitine transport and fatty acid oxidation

“…The brain does not directly uses fatty acids for oxidative metabolism, but utilizes ketone bodies derived from acetyl-CoA and acetoacetyl-CoA produced by β-oxidation of fatty acids in the liver [3]. Fatty acids originate from three primary sources: exogenous fatty acids that enter cells from the blood or from the gut lumen, fatty acids that arise via de novo synthesis from acetyl-CoA, and fatty acids that are released within the cell by the hydrolysis of acylated proteins, phospholipids, and triglycerides [17]. Endogenous fatty acids are mobilized from adipose tissue stores and transported in the circulation primarily bound to albumin (Fig.…”

“…FATPs have acyl-CoA synthase (ACS) activity [20], converting fatty acids to acyl-CoA thioesters in order to activate them for metabolic processes [2, 20, 22]. The intrinsic ACS activity of FATPs maintains a constant gradient of free fatty acids from the extracellular to the intracellular milieu, with trapping of the long-chain fatty acyl-CoA thioesters inside the cell (vectorial acylation) [17, 20, 23–26], a process conserved from Saccharomyces cerevisiae [27]. FATP1 is highly expressed in the skeletal muscle, heart, white adipose tissue and brown adipose tissue, with an increase in expression upon differentiation of 3T3-L1 cells from pre-adipocytes to adipocytes [20].…”