Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins

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.

Broadening the Scope of Dyslipidemia Therapy by Targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-Like Protein 3)

“…Although essentially all chylomicron remnants are taken up by the liver, VLDL remnants and IDL can either be removed by the liver or converted to LDL, likely through the actions of HL. Human studies with VLDL labeled with radioactive iodine or stable isotopes of amino acids indicate that the percent of VLDL converted to LDL ranges from 25% to 75%; the determinants of this wide range of conversion and, conversely, of hepatic removal of VLDL remnants and IDL, is not fully characterized, but HL 25 and EL 26 are involved.…”

Lipase-mediated selective hydrolysis of lipid droplets in phase separated-liposomes

“…However, all (mammalian) lipases from the TGL family have very similar amino acid sequences ( 36 and Figure S23 for protein alignment), structural homology, and similar functional roles on triglyceride metabolism. 33,[66][67][68] This allows the assumption that other TGLs will behave similarly on PAP3 liposomes as the LPL studied here.…”

Phase‐Separated Lipid‐Based Nanoparticles: Selective Behavior at the Nano‐Bio Interface

“…However, all (mammalian) lipases from the TGL family have very similar amino acid sequences ( [40] and Figure S30 for protein alignment, Supporting Information), structural homology, and similar functional roles on triglyceride metabolism. [37,[76][77][78] This allows the assumption that other TGLs will behave similarly on PAP3 liposomes as the LPL studied here. On the same note, the LPL chosen for these studies was derived from bovine milk (Bos Taurus), yet the sequence homology with human LPL (Homo Sapiens) is >90%, with high structural similarity and a conserved Trp-loop (see Figures S31 and S32 for protein structure alignment, Supporting Information), which allows to assume that it will similarly affect PAP3 liposomes as bovine LPL.…”