The potential roles of transacylation in intracellular lipolysis and related QSSA approximations

TL;DR

This paper investigates the role of transacylation in intracellular lipolysis, demonstrating its potential to regulate fatty acid release and stability of lipolytic processes through mathematical modeling and asymptotic analysis.

Contribution

It introduces a mathematical framework analyzing transacylation's impact on lipolysis, including novel QSSA approximations and sensitivity analysis, highlighting its biological significance.

Findings

Transacylation can alter downstream lipid products by over 50%.

QSSA with higher order corrections improves model accuracy.

Parameter sensitivity analysis is crucial for QSSA validity.

Abstract

Fatty acids (FAs) are crucial energy metabolites, signalling molecules, and membrane building blocks for a wide range of organisms. Adipose triglyceride lipase (ATGL) is the first and presumingly most crucial regulator of FA release from triacylglycerols (TGs) stored within cytosolic lipid droplets. However, besides the function of releasing FAs by hydrolysing TGs into diacylglycerols (DGs), ATGL also promotes the transacylation reaction of two DG molecules into one TG and one monoacylglycerol molecule. To date, it is unknown whether DG transacylation is a coincidental byproduct of ATGL-mediated lipolysis or whether it is physiologically relevant. Experimental evidence is scarce since both, hydrolysis and transacylation, rely on the same active site of ATGL and always occur in parallel in an ensemble of molecules. This paper illustrates the potential roles of transacylation. It shows that, depending on the kinetic parameters but also on the state of the hydrolytic machinery, transacylation can increase or decrease downstream products up to 50\% and more. We provide an extensive asymptotic analysis including quasi-steady-state approximations (QSSA) with higher order correction terms and provide numerical simulation. We also argue that when assessing the validity of QSSAs one should include parameter sensitivity derivatives. Our results suggest that the transacylation function of ATGL is of biological relevance by providing feedback options and altogether stability to the lipolytic machinery in adipocytes.