Acylcarnitines—old actors auditioning for new roles in metabolic physiology

Abstract

Perturbations in metabolic pathways can cause substantial increases in plasma and tissue concentrations of long-chain acylcarnitines (LCACs). For example, the levels of LCACs and other acylcarnitines rise in the blood and muscle during exercise, as changes in tissue pools of acylcoenzyme A reflect accelerated fuel flux that is incompletely coupled to mitochondrial energy demand and capacity of the tricarboxylic acid cycle. This natural ebb and flow of acylcarnitine generation and accumulation contrasts with that of inherited fatty acid oxidation disorders (FAODs), cardiac ischaemia or type 2 diabetes mellitus. These conditions are characterized by very high (FAODs, ischaemia) or modestly increased (type 2 diabetes mellitus) tissue and blood levels of LCACs. Although specific plasma LCAC concentrations and chain-lengths are widely used as diagnostic markers of FAODs, research into the potential effects of excessive LCAC accumulation or the roles of acylcarnitines as physiological modulators of cell metabolism is lacking. Nevertheless, a growing body of evidence has highlighted possible effects of LCACs on disparate aspects of pathophysiology, such as cardiac ischaemia outcomes, insulin sensitivity and inflammation. This Review, therefore, aims to provide a theoretical framework for the potential consequences of tissue build-up of LCACs among persons with metabolic disorders.

Metabolic Alterations Contribute to Enhanced Inflammatory Cytokine Production in Irgm1-deficient Macrophages

“…In contrast, short chain acylcarnitines were relatively decreased in IFN-␥-stimulated Irgm1-deficient BMM. Because LC-AC have pro-inflammatory properties (47)(48)(49)(50)(51), these data reinforce the finding that in IFN-␥-primed Irgm1-deficient macrophages, metabolic changes occur that are proinflammatory and typically only seen in macrophages following activation with LPS. We also exposed the cells to LPS and IFN-␥ to examine how the metabolic changes in IFN-␥-primed, Irgm1-deficient cells might compare with those in fully activated macrophages.…”

Circulating sterols as predictors of early allograft dysfunction and clinical outcome in patients undergoing liver transplantation

“…l -carnitine transports fatty acids into the mitochondria for subsequent β-oxidation, a process which results in its esterification to form acylcarnitine derivatives. As such, the endogenous carnitine pool is comprised of l -carnitine and various short-, medium- and long-chain acylcarnitines (McCoin et al 2015). Thus, acylcarnitines play a decisive role in free fatty acid (FFA) oxidation, responsible for the transportation of acyl-coenzyme A into mitochondria, especially in liver and muscle cells.…”

New Horizons in Diabetic Neuropathy: Mechanisms, Bioenergetics, and Pain

“…Acetyl-CoA can enter the TCA cycle and generate NADH and FADH 2 for OxPhos and ATP production, while remaining acyl-CoAs re-enter the β-oxidation cycle and undergo another round of 2-carbon cleavage. However, if there is substrate overload, acyl-CoAs are unable to re-enter the cycle, are converted to acylcarnitines (McCoin et al, 2015), accumulate in the SC, and are shuttled out of the SC into the axon (Viader et al, 2013). Hence, as SCs experience LCFA overload, they could undergo a metabolic reprogramming and increase CPT1 and CPT2 in an attempt to shuttle the increased load of LCFA for β-oxidation and energy.…”