Chemico-Biological Interactions xxx (2016) 1e12 Contents lists available at ScienceDirect Chemico-Biological Interactions journal homepage: www.elsevier.com/locate/chembioint Lipases and their inhibitors in health and disease * Daniel K. Nomura a, b, , John E. Casida a, c a Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720, USA b Department of Chemistry, University of California, Berkeley, CA 94720, USA c Department of Environmental Science, Policy, and Management, University of California, Berkeley, CA 94720, USA article info abstract Article history: Lipids play diverse and important biological roles including maintaining cellular integrity, storing fat for Received 5 January 2016 energy, acting as signaling molecules, and forming microdomains to support membrane protein Received in revised form signaling. Altering the levels of specific lipid species through activating or inactivating their biosynthetic 4 March 2016 or degradative pathways has been shown to provide either therapeutic benefit or cause disease. This Accepted 4 April 2016 review focuses on the functional, therapeutic, and (patho)physiological roles of lipases within the serine Available online xxx hydrolase superfamily and their inhibitors, with particular emphasis on the pharmacological tools, drugs, and environmental chemicals that inhibit these lipases. Keywords: © Lipase 2016 Published by Elsevier Ireland Ltd. Phospholipase Neutral lipases Lipase inhibitors 1. Introduction sphingolipids, ether lipids, oxidized lipids, and lipid moieties post- translationally added to proteins [1,2]. Lipases play critical roles in human health and disease. Beyond Specific lipases have been shown to be dysregulated or geneti- their importance in digestion, transport, and processing of dietary cally linked to various human pathologies [3,4]. Genetic deletion or lipids, lipases function in hydrolyzing a variety of lipid substrates to pharmacological inhibition of certain lipases has led to either modulate membrane integrity, lipid signaling, and the production therapeutic benefit or pathology in a variety of biological settings. and dynamics of lipid rafts. The substrates of lipases are diverse Not surprisingly, some lipases have been targeted by pharmaceu- including neutral lipids, phospholipids and lysophospholipids, tical companies for therapeutic benefit and there are several drugs that are currently approved or are in clinical trials for obesity, pain, inflammation, anxiety, and cardiovascular disease [5e7]. Many other lipases and their inhibitors are effective in animal models, Abbreviations: PNPLA, patatin-like phospholipase domain-containing protein; thus opening the possibility for further therapeutic exploitation of ATGL, adipose triglyceride lipase; WAT, white adipose tissue; BAT, brown adipose tissue; HSL, hormone-sensitive lipase; CES, carboxylesterase; PNLIP, pancreatic lipid hydrolyzing enzymes. However, inhibition of some lipases by lipase; CEL, carboxylester lipase; LIPF, gastric lipase; THL, tetrahydrolipstatin; LIPC, environmental chemicals has also been shown to cause pathologies hepatic lipase; LIPG, endothelial lipase; HDL, high-density lipoprotein; LPL, lipo- ranging from neurodegeneration to psychotropic effects to dysli- protein lipase; LIPA, lysosomal acid lipase; LDL, low density lipoprotein; CESD, pidemia [8,9]. cholesteryl ester storage disease; DDHD2, DDHD-domain containing protein 2; 2- Most lipases belong to the serine hydrolase superfamily of en- AG, 2-arachidonoylglycerol; CB1/CB2, cannabinoid receptor type 1/2; LPS, lipo- polysaccharide; MAGL, monoacylglycerol lipase; DAGL, diacylglycerol lipase; GABA, zymes that use the nucleophilic active-site serine to catalyze the gamma-aminobutyric acid; DSI, depolarization-induced suppression of inhibition; hydrolysis of diverse lipid substrates [2]. The conserved biochem- MAGE, monoalkylglycerol ether; NCEH1, neutral cholesteryl ester hydrolase; PAF, istry across this enzyme class, coupled with certain chemical scaf- platelet activating factor; FAAH, fatty acid amide hydrolase; PLA1, phospholipase folds that target serine hydrolases, have enabled the development A1; PLA2, phospholipase A2; PLC, phospholipase C; PLD, phospholipase D; PC, phosphatidylcholine; PE, phosphatidylethanolamine; NTE, neuropathy target of inhibitors against many lipases. However, the reactivity of the esterase; PAFAH, platelet activating factor acetylhydrolase; LPC, lysophosphati- serine nucleophile within lipase active-sites has also been a toxi- dylcholine; ABHD, alpha/beta hydrolase domain containing protein; NAPE, N- cological liability for various environmental electrophiles that acylphosphatidylethanolamines; TOCP, tri-o-cresylphosphate. covalently target the active-site serine. We review here the * Corresponding author. Department of Nutritional Sciences and Toxicology, biochemical and physiological function of lipid hydrolases with University of California, Berkeley, CA 94720, USA. E-mail addresses: [email protected], [email protected] (D.K. Nomura). particular emphasis on the pharmacological tools, drugs, and http://dx.doi.org/10.1016/j.cbi.2016.04.004 0009-2797/© 2016 Published by Elsevier Ireland Ltd. Please cite this article in press as: D.K. Nomura, J.E. Casida, Lipases and their inhibitors in health and disease, Chemico-Biological Interactions (2016), http://dx.doi.org/10.1016/j.cbi.2016.04.004 2 D.K. Nomura, J.E. Casida / Chemico-Biological Interactions xxx (2016) 1e12 environmental chemicals that inhibit lipases within the serine 2. Neutral lipid lipases hydrolase superfamily. We use the gene names for many of the li- pases described here that have had multiple designations, and the 2.1. PNPLA2 or adipose triglyceride lipase (ATGL) substrates and products for most but not all of them are shown in Figs. 1e3. PNPLA2 or adipose triglyceride lipase (ATGL) is the rate-limiting Fig. 1. Neutral lipid lipase pathways (A) and inhibitors (B). Please cite this article in press as: D.K. Nomura, J.E. Casida, Lipases and their inhibitors in health and disease, Chemico-Biological Interactions (2016), http://dx.doi.org/10.1016/j.cbi.2016.04.004 D.K. Nomura, J.E. Casida / Chemico-Biological Interactions xxx (2016) 1e12 3 ABN-acylethanolamine pathway FAAH inhibitors R O R2 O O NH O O 2 O O O O R1 H O O O- O N O- P P O O O O + O N NH3 URB597 phosphatidylethanolamine phosphatidylcholine N N calcium-dependent O O R1 transacylase O O O O O- OL-135 O O R O P N 2 O O H F C N N-acyl phosphatidylethanolamine 3 N N H PLD N O O PF-3845 HO N H anandamide O F C N (endocannabinoid) 3 N N N H FAAH N O O PF-04457845 OH arachidonic acid Fig. 2. N-Acylethanolamine pathway (A) and FAAH inhibitors (B). step for triglyceride hydrolysis in adipose tissues with the highest LIPE to be translocated from the cytosol to lipid droplets to activate expression in both white and brown adipose tissues (WAT/BAT), its hydrolytic activity [17,18]. LIPE(À/À) mice show complete abla- with lesser expression in skeletal and cardiac muscle and testes tion of cholesteryl ester hydrolytic activity in WAT, BAT, and testes, (Fig. 1A). PNPLA2(À/À) mice show >80, 44, and 73% decrease in but still possess ~40% triacylglycerol hydrolytic activity in adipose triacylglycerol hydrolytic activity in WAT, skeletal muscle, and liver, tissue, consistent with the primary role of ATGL in adipose tri- respectively, and show reduced release of fatty acids following acylglycerol hydrolysis [19]. These mice show adipocyte hypertro- isoproterenol stimulation. PNPLA2(À/À) mice show mild obesity phy, but not obesity, and reduced isoproterenol-stimulated fatty with increased fat mass and larger WAT and BAT lipid droplets, and acid release in WAT and accumulation of diacylglycerols in several are intolerant to cold exposure or fasting, likely due to their lipo- tissues [19,20]. LIPE(À/À) mice are also infertile due to lack of lytic impairment and inability to release fatty acids for heat and spermatozoa [19], are resistant to high-fat diet-induced obesity, energy production. These mice die prematurely from a large show improved hepatic insulin sensitivity, and are protected from accumulation of triacylglycerols in the heart leading to cardiac short-term diet-induced insulin resistance in skeletal muscle and dysfunction [10]. heart [21,22]. Nonetheless, inhibiting ATGL may have potential therapeutic Inhibitors of HSL include heterocyclic ureas and carbamates benefit. PNPLA2(À/À) mice show improved glucose tolerance and such as Ebdrup 13f from Novo Nordisk and BAY from Bayer insulin sensitivity under both normal and high-fat diet [10e12]. Healthcare, but their selectivity remains unknown (Fig. 1B) [23,24]. PNPLA2-deficient mice are also protected against adipose and BAY has been shown to inhibit forskolin-activated lipolysis both muscle loss caused by cancer-associated cachexia [13]. Atglstatin is in vitro and ex vivo, lower plasma free fatty acid and glycerol levels an ATGL inhibitor that has been reported to selectively inhibit tri- in vivo in overnight-fasted mice and dogs, and reduce hyperglyce- glyceride hydrolase activity in WAT and reduce free fatty acid mia in streptozotocin-induced diabetic rats [23]. Ebdrup 13f has release in vitro and in vivo in wild-type but not PNPLA2(À/À) mice, been shown to reduce lipolysis in vivo in fasted rats [24]. indicating the specificity of the inhibitor [14] (Fig. 1B). Of future importance will be to understand whether pharmacological 2.3. Triglyceride hydrolase or carboxylesterase 3 (Ces3) blockade of ATGL