Subbaiah PV

References (6)

Title : Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins - Khetarpal_2021_PLoS.Genet_17_e1009802
Author(s) : Khetarpal SA , Vitali C , Levin MG , Klarin D , Park J , Pampana A , Millar JS , Kuwano T , Sugasini D , Subbaiah PV , Billheimer JT , Natarajan P , Rader DJ
Ref : PLoS Genet , 17 :e1009802 , 2021
Abstract : Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.
ESTHER : Khetarpal_2021_PLoS.Genet_17_e1009802
PubMedSearch : Khetarpal_2021_PLoS.Genet_17_e1009802
PubMedID: 34543263
Gene_locus related to this paper: mouse-Lipg , human-LIPG

Title : Potential role of hepatic lipase in the accretion of docosahexaenoic acid (DHA) by the brain - Sugasini_2021_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids__159002
Author(s) : Sugasini D , Yang P , Ng D , Khetarpal S , Vitali C , Rader D , Subbaiah PV
Ref : Biochimica & Biophysica Acta Molecular & Cellular Biology Lipids , :159002 , 2021
Abstract : DHA (docosahexaenoic acid) is an essential fatty acid that is required for the normal development and function of the brain. Because of its inability to synthesize adequate amounts of DHA from the precursors, the brain has to acquire DHA from plasma through the blood brain barrier (BBB). Recent studies demonstrated the presence of a transporter at the BBB that specifically transports DHA into the brain in the form of lysophosphatidylcholine (LPC-DHA). However, the mechanism by which LPC-DHA is generated in the plasma is not known. Our previous studies showed that there are at least three different enzymes - lecithin cholesterol acyltransferase (LCAT), endothelial lipase (EL), and hepatic lipase (HL), which can generate LPC-DHA from sn-2 DHA phosphatidylcholine. Here we determined the relative contributions of these enzymes in the delivery of DHA to the brain by measuring the brain DHA levels in the mice deficient in each of these enzymes. The results show that the brain DHA levels of LCAT-deficient mice or EL-deficient mice were not significantly lower than those of their littermates. However, brain DHA was significantly decreased in HL deficient mice (13.5% of total fatty acids) compared to their littermates (17.1%) (p<0.002), and further decreased to 8.3% of total fatty acids in mice deficient in both HL and EL. These results suggest that HL activity may be the major source for the generation of LPC-DHA in the plasma necessary for transport into the brain, and EL might contribute to this process in the absence of HL.
ESTHER : Sugasini_2021_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids__159002
PubMedSearch : Sugasini_2021_Biochim.Biophys.Acta.Mol.Cell.Biol.Lipids__159002
PubMedID: 34197964

Title : Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins - Yang_2015_Biochim.Biophys.Acta_1851_1327
Author(s) : Yang P , Subbaiah PV
Ref : Biochimica & Biophysica Acta , 1851 :1327 , 2015
Abstract : Hepatic lipase (HL) is an important enzyme in the clearance of triacylglycerol (TAG) from the circulation, and has been proposed to have pro-atherogenic as well as anti-atherogenic properties. It hydrolyzes both phospholipids and TAG of lipoproteins, and its activity is negatively correlated with HDL levels. Although it is known that HL acts preferentially on HDL lipids, the basis for this specificity is not known, since it does not require any specific apoprotein for activity. In this study, we tested the hypothesis that sphingomyelin (SM), whose concentration is much higher in VLDL and LDL compared to HDL, is an inhibitor of HL, and that this could explain the lipoprotein specificity of the enzyme. The results presented show that the depletion of SM from normal lipoproteins activated the HL roughly in proportion to their SM content. SM depletion stimulated the hydrolysis of both phosphatidylcholine (PC) and TAG, although the PC hydrolysis was stimulated more. In the native lipoproteins, HL showed specificity for PC species containing polyunsaturated fatty acids at sn-2 position, and produced more unsaturated lyso PC species. The enzyme also showed preferential hydrolysis of certain TAG species over others. SM depletion affected the specificity of the enzyme towards PC and TAG species modestly. These results show that SM is a physiological inhibitor of HL activity in lipoproteins and that the specificity of the enzyme towards HDL is at least partly due to its low SM content.
ESTHER : Yang_2015_Biochim.Biophys.Acta_1851_1327
PubMedSearch : Yang_2015_Biochim.Biophys.Acta_1851_1327
PubMedID: 26193433

Title : Inhibition of endothelial lipase activity by sphingomyelin in the lipoproteins - Yang_2014_Lipids_49_987
Author(s) : Yang P , Belikova NA , Billheimer J , Rader DJ , Hill JS , Subbaiah PV
Ref : Lipids , 49 :987 , 2014
Abstract : Endothelial lipase (EL) is a major determinant of plasma HDL concentration, its activity being inversely proportional to HDL levels. Although it is known that it preferentially acts on HDL compared to LDL and VLDL, the basis for this specificity is not known. Here we tested the hypothesis that sphingomyelin, a major phospholipid in lipoproteins is a physiological inhibitor of EL, and that the preference of the enzyme for HDL may be due to low sphingomyelin/phosphatidylcholine (PtdCho) ratio in HDL, compared to other lipoproteins. Using recombinant human EL, we showed that sphingomyelin inhibits the hydrolysis of PtdCho in the liposomes in a concentration-dependent manner. While the enzyme showed lower hydrolysis of LDL PtdCho, compared to HDL PtdCho, this difference disappeared after the degradation of lipoprotein sphingomyelin by bacterial sphingomyelinase. Analysis of molecular species of PtdCho hydrolyzed by EL in the lipoproteins showed that the enzyme preferentially hydrolyzed PtdCho containing polyunsaturated fatty acids (PUFA) such as 22:6, 20:5, 20:4 at the sn-2 position, generating the corresponding PUFA-lyso PtdCho. This specificity for PUFA-PtdCho species was not observed after depletion of sphingomyelin by sphingomyelinase. These results show that sphingomyelin not only plays a role in regulating EL activity, but also influences its specificity towards PtdCho species.
ESTHER : Yang_2014_Lipids_49_987
PubMedSearch : Yang_2014_Lipids_49_987
PubMedID: 25167836
Gene_locus related to this paper: human-LIPG

Title : Phospholipid and fatty acid specificity of endothelial lipase: potential role of the enzyme in the delivery of docosahexaenoic acid (DHA) to tissues - Chen_2007_Biochim.Biophys.Acta_1771_1319
Author(s) : Chen S , Subbaiah PV
Ref : Biochimica & Biophysica Acta , 1771 :1319 , 2007
Abstract : Docosahexaenoic acid (DHA; 22:6 n-3) is an essential fatty acid required for the normal function of several tissues, especially the brain. Previous studies suggested that lysophosphatidylcholine (lysoPC) is a preferred carrier of DHA to the brain, although the pathways of the formation of DHA-containing lysophospholipids in plasma have not been delineated. We propose that endothelial lipase (EL), a phospholipase A1 that plays an important role in the metabolism of high density lipoproteins, may be responsible for the generation of DHA lysophospholipids in plasma. Here we studied the substrate specificity of EL using deuterium-labeled phospholipids with different polar head groups, as well as DHA-enriched natural phospholipids to test this hypothesis. Glycerol-stabilized phospholipids were treated with recombinant EL, and the products were analyzed by liquid chromatography/electrospray ionization mass spectrometry. EL showed the polar head group specificity in the order of phosphatidylethanolamine>phosphatidylcholine>phosphatidylserine>phosphatidic acid. Within the same phospholipid class, the enzyme showed preference for the species containing DHA at the sn-2 position, and was inactive in the hydrolysis of phospholipids containing an ether linkage. Since EL is known to be secreted by the cells of blood-brain barrier, we suggest that it plays an important role in the delivery of DHA lysophospholipid carriers to the brain.
ESTHER : Chen_2007_Biochim.Biophys.Acta_1771_1319
PubMedSearch : Chen_2007_Biochim.Biophys.Acta_1771_1319
PubMedID: 17905648
Gene_locus related to this paper: human-LIPG

Title : Novel function of lecithin-cholesterol acyltransferase. Hydrolysis of oxidized polar phospholipids generated during lipoprotein oxidation - Goyal_1997_J.Biol.Chem_272_16231
Author(s) : Goyal J , Wang K , Liu M , Subbaiah PV
Ref : Journal of Biological Chemistry , 272 :16231 , 1997
Abstract : Although the major function of lecithin-cholesterol acyltransferase (LCAT) is cholesterol esterification, our previous studies showed that it can also hydrolyze platelet-activating factor (PAF). Because of the structural similarities between PAF and the truncated phosphatidylcholines (polar PCs) generated during lipoprotein oxidation, we investigated the possibility that LCAT may also hydrolyze polar PCs to lyso-PC during the oxidation of plasma. PAF acetylhydrolase (PAF-AH), which is known to hydrolyze polar PCs in human plasma, was completely inhibited by 0.2 mM p-aminoethyl benzenesulfonyl fluoride (Pefabloc), a new serine esterase inhibitor, which had no effect on LCAT at this concentration. On the other hand, 1 mM diisopropylfluorophosphate (DFP) completely inhibited LCAT but had no effect on PAF-AH. Polar PC accumulation during the oxidation of plasma increased by 44% in the presence of 0.2 mM Pefabloc and by 30% in the presence of 1 mM DFP. The formation of lyso-PC was concomitantly inhibited by both of the inhibitors. The combination of the two inhibitors resulted in the maximum accumulation of polar PCs, suggesting that both PAF-AH and LCAT are involved in their breakdown. Oxidation of chicken plasma, which has no PAF-AH activity, also resulted in the formation of lyso-PC from the hydrolysis of polar PC, which was inhibited by DFP. Polar PCs, either isolated from oxidized plasma or by oxidation of labeled synthetic PCs, were hydrolyzed by purified LCAT, which had no detectable PAF-AH activity. These results demonstrate a novel function for LCAT in the detoxification of polar PCs generated during lipoprotein oxidation, especially when the PAF-AH is absent or inactivated.
ESTHER : Goyal_1997_J.Biol.Chem_272_16231
PubMedSearch : Goyal_1997_J.Biol.Chem_272_16231
PubMedID: 9195924