The Importance of Lipoprotein Lipase Regulation in Atherosclerosis

Figures

• 

  Figure 1. Chylomicron and VLDL life cycle. Chylomicrons are secreted from the intestines to the circulation where they extract apolipoproteins from HDL. The mature chylomicrons are arrested at the capillary endothelium by LPL that is in complex with glycosylphosphatidylinositol anchored high density lipoprotein binding protein 1 (GPIHBP1). LPL performs lipolysis on the encapsulated TGs, which releases free fatty acids that are taken up by the underlying tissues (white adipose tissue (WAT), skeletal muscle (SKM), and the heart). Upon complete hydrolysis, a chylomicron remnant particle is released to the circulation. The chylomicron remnant particle back-exchanges apolipoproteins to circulating HDL, before final catabolism in the liver. A similar life cycle is found for VLDL. VLDL is secreted from the liver and is arrested and hydrolyzed by the LPL•GPIHBP1 complex. This releases IDL, which can either be taken up by the liver or be hydrolyzed further into LDL. LDL deposits cholesterol esters in various tissues. HDL absorbs cholesterol and transports it to the liver.

• 

  Figure 2. Structural elements in LPL. Cartoon representation of the human LPL•GPIHBP1 complex and with the molecular surface of the LU domain (Ly6/uPAR protein domain family) of GPIHBP1 shown as a transparent light blue envelope (generated with The PyMol Molecular Graphic System (Version 2.0 Schrödinger, LLC) using coordinates from the LPL•GPIHBP1 crystal structure; Protein Data Bank ID code 6E7K). LPL elements implicated in ANGPTL4 binding are highlighted in yellow [17]. GPIHBP1 binds to the C-terminal PLAT domain of LPL, and the location of GPIHBP1’s membrane-tethering site (GPI anchor) is indicated [18]. GPIHBP1’s acidic intrinsically disordered domain stabilizes LPL’s α/β-hydrolase domain and is assumed to interact with a large basic patch on the surface of LPL [19,20]. The active site containing the catalytic triad (Ser134, Asp158, and His243) is represented with orange residues [21] and the orange helix is the lid covering the active site responsible for substrate specificity [22]. The triglyceride-rich lipoprotein (TRL) binding site is indicated in green and residues important for heparin binding is shown in blue [23,24,25].

• 

  Figure 3. Schematic overview of LPL translocation. LPL is secreted from adipose tissue and myocytes from skeletal muscles and heart. Intracellular LPL folding and secretion is assisted by LMF1, Sel1L and SCD1. After secretion, active LPL is bound to cell surface HSPG before being translocated to GPIHBP1, potentially via Collagen XVIII. GPIHBP1 captures LPL in the subendothelial space and mediates LPL trancytosis across the capillary endothelium, into the lumen. Within the lumen, the LPL•GPIHBP1 complex is responsible for the arrest of VLDLs and chylomicrons. After final hydrolysis, either a chylomicron remnant particle or an IDL are released to be taken up by the liver or turned into LDL via further TG hydrolysis, respectively. ANGPTL4 act as a potent LPL inhibitor in the adipose tissue, and ANGPTL3•ANGPTL8 act on LPL mainly in the capillaries of the muscles and heart. The inhibition of the ANGPTLs is driven by nutritional status and exercise. MAG: Monoacylglycerol.