GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity.

Kristian Kølby Kristensen,Anne Louise Grønnemose,Anne-Marie Lund-Winther,Katrine Zinck Leth-Espensen,Michael Ploug,Stephen G Young,Anni Kumari

doi:10.3389/fcell.2021.702508

Abstract

Intravascular processing of triglyceride-rich lipoproteins (TRLs) is crucial for delivery of dietary lipids fueling energy metabolism in heart and skeletal muscle and for storage in white adipose tissue. During the last decade, mechanisms underlying focal lipolytic processing of TRLs along the luminal surface of capillaries have been clarified by fresh insights into the functions of lipoprotein lipase (LPL); LPL’s dedicated transporter protein, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1); and its endogenous inhibitors, angiopoietin-like (ANGPTL) proteins 3, 4, and 8. Key discoveries in LPL biology include solving the crystal structure of LPL, showing LPL is catalytically active as a monomer rather than as a homodimer, and that the borderline stability of LPL’s hydrolase domain is crucial for the regulation of LPL activity. Another key discovery was understanding how ANGPTL4 regulates LPL activity. The binding of ANGPTL4 to LPL sequences adjacent to the catalytic cavity triggers cooperative and sequential unfolding of LPL’s hydrolase domain resulting in irreversible collapse of the catalytic cavity and loss of LPL activity. Recent studies have highlighted the importance of the ANGPTL3–ANGPTL8 complex for endocrine regulation of LPL activity in oxidative organs (e.g., heart, skeletal muscle, brown adipose tissue), but the molecular mechanisms have not been fully defined. New insights have also been gained into LPL–GPIHBP1 interactions and how GPIHBP1 moves LPL to its site of action in the capillary lumen. GPIHBP1 is an atypical member of the LU (Ly6/uPAR) domain protein superfamily, containing an intrinsically disordered and highly acidic N-terminal extension and a disulfide bond–rich three-fingered LU domain. Both the disordered acidic domain and the folded LU domain are crucial for the stability and transport of LPL, and for modulating its susceptibility to ANGPTL4-mediated unfolding. This review focuses on recent advances in the biology and biochemistry of crucial proteins for intravascular lipolysis.

Highlights

Dietary lipids are absorbed by the intestinal epithelium and packaged into triglyceride-rich lipoprotein (TRLs) called chylomicrons (Dash et al, 2015)
Secreted TRLs enter into the bloodstream and marginate along the luminal surfaces of capillaries, where triglycerides are hydrolyzed by lipoprotein lipase (LPL)
We focus on the dynamic interplay between LPL, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1), and ANGPTLs 3, 4, and 8

Summary

INTRODUCTION

Dietary lipids are absorbed by the intestinal epithelium and packaged into triglyceride-rich lipoprotein (TRLs) called chylomicrons (Dash et al, 2015). Secreted TRLs enter into the bloodstream and marginate along the luminal surfaces of capillaries, where triglycerides are hydrolyzed by lipoprotein lipase (LPL). This process releases free fatty acids and monoacylglycerol for use as fuel in heart, skeletal muscle and brown adipose tissue or for storage in white adipose tissue (WAT). In contrast to the adverse effects of impaired TLR processing, increased efficiency of TRL processing is associated with lower plasma triglyceride levels and reduced risk of ASCVD (Crosby et al, 2014; Jorgensen et al, 2014; Dewey et al, 2017; Graham et al, 2017). The parenchymal cells (myocytes and adipocytes) adjacent to capillaries (Figure 1)

LIPOPROTEIN LIPASE

Structure and Stability of LPL

Oligomeric States of LPL

Chaperoning of Nascent LPL During Synthesis and Secretion

Findings

Subendothelial Partitioning of LPL