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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.
Highlights
Lipolysis of circulating triglyceride (TG)-rich lipoproteins (TRLs) is critical for the delivery of fatty acids to tissues and control of circulating TG levels [1, 2]
We show through studies of humans and mice with genetic loss-of-function of endothelial lipase (EL) activity that EL is crucial in catabolizing triglyceride (TG)-rich lipoproteins, in states of nutrient excess such as after refeeding or after feeding a high-fat diet
We demonstrate that EL collaborates with lipoprotein lipase (LPL), the predominant enzyme hydrolysing triglycerides, to promote the breakdown of triglycerides on lipoproteins
Summary
Lipolysis of circulating triglyceride (TG)-rich lipoproteins (TRLs) is critical for the delivery of fatty acids to tissues and control of circulating TG levels [1, 2]. Recent insights from epidemiology and human genetics have shown that high TRL levels increase cardiovascular risk while lower TG levels are associated with risk reduction independently of low-density lipoprotein cholesterol (LDL-C) levels [4, 5]. Genetic loss- or gain-of-function of LPL in animal models and in humans has demonstrated the key role it plays in TG clearance, with genetic loss-of-function in LPL or key adaptors leading to severe hypertriglyceridemia [1, 6, 7]. HL hydrolyzes TGs and phospholipids (PLs) on TRL remnants, intermediate density lipoproteins (IDLs) and high density lipoproteins (HDLs) [8]. Inhibition or deficiency of HL in animal models results in delayed chylomicron remnant and IDL clearance in vivo [8] and humans with genetic loss-of-function in LIPC, which encodes HL, demonstrate elevations in TRL remnants [9]
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