Biology subjects

Lass, A.

Publications and source records attributed to Lass, A..

4 recordsLinked to original sources

bioRxiv2026

Acid phospholipase A1 promotes lysosomal membrane catabolism

The molecular mechanisms of lysosomal glycerophospholipid (GPL) catabolism are incompletely understood. Here, we report that acid phospholipase A1 (APLA1), formerly known as palmitoyl-protein thioesterase 2 (PPT2), is required for efficient GPL degradation. Deletion of APLA1 in human cells results in excess accumulation of phospholipids within lysosomes # a pathological condition termed phospholipidosis. APLA1 activity depends on interactions with negatively charged GPLs and is inhibited by phospholipidosis-inducing cationic amphiphilic drugs. Hydrolysis of zwitterionic, but not anionic, GPLs requires co-activation of APLA1 by the lysosome-specific lipid bis(monoacylglycero)phosphate. Upon pharmacological mTORC inhibition, which increases lysosomal GPL turnover, APLA1-deficient cells exhibit massive accumulation of multilamellar membranes in lysosomes and reduced cytosolic triacylglycerol stores. APLA1 acts in concert with lysosomal phospholipase A2 (PLA2G15). Combined APLA1/PLA2G15-deficiency leads to a severe reduction in acid phospholipase A1/A2 activity, thereby exacerbating phospholipidosis. Our observations provide detailed mechanistic insights into lysosomal GPL catabolism, a crucial pathway for maintaining lipid homeostasis.

biochemistry↗

bioRxiv2025

CLN8 enables a non-canonical phospholipid synthesis pathway

According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol (GPG), resulting in the formation of lysophosphatidylglycerol (LPG). The acyltransferase reaction is catalyzed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived LPG is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis, but not into phosphatidylglycerol or cardiolipin. CLN8-knockout cells and mice cannot utilize GPG for BMP synthesis, resulting in BMP-deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP-deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders.

biochemistry↗

bioRxiv2024

The endolysosomal phospholipid bis(monoacylglycero)phosphate is synthesized via intra- and extracellular pathways

Bis(monoacylglycero)phosphate (BMP) is a major phospholipid constituent of intralumenal membranes in late endosomes/lysosomes, where it regulates the degradation and sorting of lipid cargo. Recent observations suggest that the Batten disease - associated protein CLN5 functions as lysosomal BMP synthase. Here, we show that transacylation reactions catalyzed by cytosolic and secreted enzymes enhance BMP synthesis independently of CLN5. The transacylases identified in this study are capable of acylating the precursor lipid phosphatidylglycerol (PG), generating acyl-PG, which is subsequently hydrolyzed to BMP. Extracellularly, acyl-PG and BMP are generated by endothelial lipase in cooperation with other serum enzymes of the pancreatic lipase family. The intracellular acylation of PG is catalyzed by several members of the cytosolic phospholipase A2 group IV (PLA2G4) family. Overexpression of secreted or cytosolic transacylases was sufficient to correct BMP deficiency in HEK293 cells lacking CLN5. Collectively, our observations suggest that functionally overlapping pathways promote BMP synthesis in mammalian cells.

biochemistry↗

bioRxiv2021

ATGL-dependent white adipose tissue lipolysis controls hepatocyte PPARα activity

ObjectiveIn hepatocytes, peroxisome proliferator-activated receptor (PPAR) acts as a lipid sensor that regulates hepatic lipid catabolism during fasting and orchestrates a genomic response required for whole-body homeostasis. This includes the biosynthesis of ketone bodies and the secretion of the starvation hormone fibroblast growth factor 21 (FGF21). Several lines of evidence suggest that adipose tissue lipolysis contributes to this specific process. However, whether adipose tissue lipolysis is a dominant signal for the extensive remodeling of liver gene expression dependent on PPAR has not been investigated. MethodsFirst, using mice lacking adipose tissue lipolysis through adipocyte-specific deletion of adipose triglyceride lipase (ATGL), we characterized the responses dependent on adipocyte ATGL during fasting. Next, we performed liver whole genome expression analysis in fasted mice upon deletion of adipocyte ATGL or hepatocyte PPAR. Finally, we tested the consequences of hepatocyte-specific PPAR deficiency during pharmacological induction of adipocyte lipolysis with a {beta}3-adrenergic receptor agonist. ResultsIn the absence of ATGL in adipocytes, ketone body and FGF21 productions were impaired in response to starvation. Liver transcriptome analysis revealed that adipocyte ATGL is critical for regulation of hepatic gene expression during fasting and highlighted a strong enrichment in PPAR target genes in this condition. Genome expression analysis confirmed that a large set of fasting-induced genes are sensitive to both ATGL and PPAR. Adipose tissue lipolysis induced by acute activation of the {beta}3-adrenergic receptor also triggered PPAR-dependent responses in the liver, supporting a role for adipocyte-derived fatty acids as dominant signals for hepatocyte PPAR activity. In addition, the absence of hepatocyte PPAR altered brown adipose tissue (BAT) morphology and reduced UCP1 expression upon stimulation of the {beta}3-adrenergic receptor. In agreement with this finding, mice lacking hepatocyte PPAR showed decreased tolerance to acute cold exposure. ConclusionsThese results underscore the central role of hepatocyte PPAR in the sensing of adipocyte-derived fatty acids and reveal that its activity is essential for full activation of BAT. Intact PPAR activity in hepatocytes is required for cross-talk between adipose tissues and the liver during fat mobilization during fasting and cold exposure.

physiology↗