Lipoprotein lipase

Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the

triacylglycerol + H₂O = diacylglycerol + a carboxylate

It is also involved in promoting the cellular uptake of

Homodimerization is required before LPL can be secreted from cells.[16]^[17] After secretion, LPL is carried across endothelial cells and presented into the capillary lumen by the protein glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1.^[18][19]

Structure

The active site of LPL is composed of the conserved Ser-132, Asp-156, and His-241 triad. Other important regions of the N-terminal domain for catalysis includes an

The LPL non-covalent homodimer has a head-to-tail arrangement of the monomers. The Ser/Asp/His triad is in a hydrophobic groove that is blocked from solvent by the lid.[5]^[11] Upon binding to ApoC-II and lipid in the lipoprotein, the C-terminal domain presents the lipid substrate to the lid region. The lipid interacts with both the lid region and the hydrophobic groove at the active site; this causes the lid to move, providing access to the active site. The β5 loop folds back into the protein core, bringing one of the electrophiles of the oxyanion hole into position for lipolysis.^[5] The glycerol backbone of the lipid is then able to enter the active site and is hydrolyzed.

Two molecules of ApoC-II can attach to each LPL dimer.

LPL gene encodes lipoprotein lipase, which is expressed in the heart, muscle, and adipose tissue.[26]^[27] LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Through catalysis, VLDL is converted to IDL and then to LDL. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism.^[28]

Regulation

LPL is controlled transcriptionally and posttranscriptionally.^[29] The circadian clock may be important in the control of Lpl mRNA levels in peripheral tissues.^[30]

LPL

Consistent with this, dietary macronutrients differentially affect adipose and muscle LPL activity. After 16 days on a high-carbohydrate or a high-fat diet, LPL activity increased significantly in both tissues 6 hours after a meal of either composition, but there was a significantly greater rise in adipose tissue LPL in response to the high-carbohydrate diet compared to the high-fat diet. There was no difference between the two diets' effects on insulin sensitivity or fasting LPL activity in either tissue.[32]

The concentration of LPL displayed on endothelial cell surface cannot be regulated by endothelial cells, as they neither synthesize nor degrade LPL. Instead, this regulation occurs by managing the flux of LPL arriving at the lipolytic site and by regulating the activity of LPL present on the endothelium. A key protein involved in controlling the activity of LPL is ANGPTL4, which serves as a local inhibitor of LPL. Induction of ANGPTL4 accounts for the inhibition of LPL activity in white adipose tissue during fasting. Growing evidence implicates ANGPTL4 in the physiological regulation of LPL activity in a variety of tissues.^[33]

An ANGPTL3-4-8 model was proposed to explain the variations of LPL activity during the fed-fast cycle.^[34] Specifically, feeding induces ANGPTL8, activating the ANGPTL8–ANGPTL3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating triglycerides available for uptake by white adipose tissue, in which LPL activity is elevated owing to diminished ANGPTL4; the reverse is true during fasting, which suppresses ANGPTL8 but induces ANGPTL4, thereby directing triglycerides to muscles. The model suggests a general framework for how triglyceride trafficking is regulated.^[34]

Clinical significance

Lipoprotein lipase deficiency leads to hypertriglyceridemia (elevated levels of triglycerides in the bloodstream).^[35] In mice, overexpression of LPL has been shown to cause insulin resistance,^[36][37] and to promote obesity.^[30]

A high adipose tissue LPL response to a high-carbohydrate diet may predispose toward fat gain. One study reported that subjects gained more body fat over the next four years if, after following a high-carbohydrate diet and partaking of a high-carbohydrate meal, they responded with an increase in adipose tissue LPL activity per adipocyte, or a decrease in skeletal muscle LPL activity per gram of tissue.^[38]

LPL expression has been shown to be a prognostic predictor in Chronic lymphocytic leukemia.^[39] In this haematological disorder, LPL appears to provide fatty acids as an energy source to malignant cells.^[40] Thus, elevated levels of LPL mRNA or protein are considered to be indicators of poor prognosis.^{[41][42][43][44][45][46][47][48][49][50]}

Interactions

Lipoprotein lipase has been shown to

The LPL gene is highly conserved across vertebrates. Lipoprotein lipase is involved in lipid transport in the placentae of live bearing lizards (Pseudemoia entrecasteauxii).^[54]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. ^{[§ 1]}

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|alt=Statin pathway edit]]

Statin pathway edit

1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".

References