Franz Peter Walter Radner

Adipose triglyceride lipase (ATGL) catalyses the first and rate-limiting step of intracellular triacylglycerol (TAG) hydrolysis, yielding diacylglycerol (DAG) and a free fatty acid (FA). The site of TAG cleavage determines the regioisomeric identity of the DAG product, with distinct consequences for downstream signalling and lipid metabolism. Here, we show that ATGL prefers specific fatty acyl chain lengths and that this preference contributes to its regioselectivity on heterogeneous TAG substrates. Structural modelling identified a substrate-binding pocket comprising a hydrophilic anchor and a hydrophobic tunnel whose dimensions favour long-chain FAs. Mass spectrometry-based analysis of DAG products generated by ATGL from defined TAG substrates revealed an intrinsic preference for terminal ( sn -1/ sn -3) ester bond cleavage. Acyl-chain compatibility modulated this preference, with poorly accommodated terminal chains increasing the relative contribution of sn -2 cleavage. Consequently, ATGL generated predominantly sn -2-retaining DAG species from heterogeneous TAG substrates containing long-chain fatty acyl chains, including substantial amounts of the sn -1,2-DAG regioisomer, which has not previously been associated with ATGL activity. These findings link the fatty acyl chain composition of TAGs to the DAG regioisomer profile generated by ATGL-mediated lipolysis and provide substrate-dependent parameters for more species-resolved models of lipid metabolism.

The α/β-Hydrolase domain-containing protein 5 (ABHD5; also known as comparative gene identification-58, or CGI-58) is the causative gene of the Chanarin-Dorfman syndrome (CDS), a disorder mainly characterized by systemic triacylglycerol accumulation and a severe defect in skin barrier function. The clinical phenotype of CDS patients and the characterization of global and tissue-specific ABHD5-deficient mouse strains have demonstrated that ABHD5 is a crucial regulator of lipid and energy homeostasis in various tissues. Although ABHD5 lacks intrinsic hydrolase activity, it functions as a co-activating enzyme of the patatin-like phospholipase domain-containing (PNPLA) protein family that is involved in triacylglycerol and glycerophospholipid, as well as sphingolipid and retinyl ester metabolism. Moreover, ABHD5 interacts with perilipins (PLINs) and fatty acid-binding proteins (FABPs), which are important regulators of lipid homeostasis in adipose and non-adipose tissues. This review focuses on the multifaceted role of ABHD5 in modulating the function of key enzymes in lipid metabolism.

Significance: Fat mass is controlled by the balance of triacylglycerol (TAG) degradation and synthesis. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are key players in TAG catabolism providing fatty acids (FAs) as energy substrates and metabolic intermediates. Here, we show that ATGL and HSL metabolize TAGs containing antidiabetic lipid mediators (FA esters of hydroxy FAs), distinctly controlling the release of bioactive lipids. Our paper connects lipolysis-mediated TAG metabolism with the regulation of antidiabetic signaling lipids.