Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1

He, Cuiwen; Hu, Xuchen; Jung, Rachel S.; Larsson, Mikael; Tu, Yiping; Duarte-Vogel, Sandra; Kim, Paul; Sandoval, Norma P.; Price, Tara R.; Allan, Christopher M.; Raney, Brian J.; Jiang, Haibo; Bensadoun, André; Walzem, Rosemary L.; Kuo, Richard; Beigneux, Anne P.; Fong, Loren G.; Young, Stephen G.

doi:10.1172/jci.insight.96783

Cited by 10 publications

(7 citation statements)

References 47 publications

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“…While LPL emerged relatively early in evolution and is present in teleosts (Holmes et al, 2011), GPIHBP1 evolved later and is confined to mammals (Holmes and Cox, 2012). This evolutionary delay raises the question of how lower vertebrates such as birds, fishes, and reptiles transport LPL to the capillary lumen (He et al, 2017b).…”

Section: Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Proteinmentioning

confidence: 99%

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

Kristensen

Leth-Espensen

Kumari

et al. 2021

Front. Cell Dev. Biol.

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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.

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Section: Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Proteinmentioning

confidence: 99%

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

Kristensen

Leth-Espensen

Kumari

et al. 2021

Front. Cell Dev. Biol.

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“…The sequence of the putative enhancer was conserved in humans and other mammals (supplemental Fig. S1), but not in lower vertebrates, where a gene for GPIHBP1 has never been identified and seemingly does not exist (38). We also retrieved and analyzed Roadmap Epigenomics data (24) for humans and identified marks for open chromatin and H3K27ac in muscle, liver, and lung (Fig.…”

Section: Resultsmentioning

confidence: 99%

An upstream enhancer regulates Gpihbp1 expression in a tissue-specific manner

Allan

Heizer

et al. 2019

Journal of Lipid Research

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Supplementary key words chylomicrons • endothelial cells • lipids • lipolysis • fatty acid metabolism • triglycerides • glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1The intravascular processing of triglyceride-rich lipoproteins (TRLs) by LPL is the central event in plasma lipid metabolism, providing nutrients for vital tissues and generating the lipoprotein remnants that play a causal role in atherogenesis (1, 2). LPL is produced by parenchymal cells (e.g., adipocytes, myocytes) and secreted into the interstitial spaces. The interstitial LPL is almost certainly bound by heparan sulfate proteoglycans near the surface of parenchymal cells, but those interactions are weak and transient, making it possible for LPL to move to glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) on the basolateral surface of capillary endothelial cells (3, 4). After being captured by GPI-HBP1, the LPL is shuttled across endothelial cells to its site of action in the capillary lumen (5). In the absence of GPI-HBP1, LPL remains stranded within the interstitial spaces, Abstract Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1), the protein that shuttles LPL to the capillary lumen, is essential for plasma triglyceride metabolism. When GPIHBP1 is absent, LPL remains stranded within the interstitial spaces and plasma triglyceride hydrolysis is impaired, resulting in severe hypertriglyceridemia. While the functions of GPIHBP1 in intravascular lipolysis are reasonably well understood, no one has yet identified DNA sequences regulating GPIHBP1 expression. In the current studies, we identified an enhancer element located 3.6 kb upstream from exon 1 of mouse Gpihbp1. To examine the importance of the enhancer, we used CRISPR/Cas9 genome editing to create mice lacking the enhancer (Gpihbp1 Enh/Enh ). Removing the enhancer reduced Gpihbp1 expression by >90% in the liver and by 50% in heart and brown adipose tissue. The reduced expression of GPIHBP1 was insufficient to prevent LPL from reaching the capillary lumen, and it did not lead to hypertriglyceridemia-even when mice were fed a high-fat diet. Compound heterozygotes (Gpihbp1 Enh/ mice) displayed further reductions in Gpihbp1 expression and exhibited partial mislocalization of LPL (increased amounts of LPL within the interstitial spaces of the heart), but the plasma triglyceride levels were not perturbed. The enhancer element that we identified represents the first insight into DNA sequences controlling Gpihbp1 expression.

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“…LPL and GPIHBP1 were expressed with CMV promoter–based vectors ( 1 , 13 , 43 ) in CHO cells that had been modified by CRISPR/Cas9 editing to eliminate expression of hamster LPL ( 44 ). A vector for S-GPIHBP1 was generated by replacing sequences for GPIHBP1 residues 32 to 48 with sequences for the S-protein tag.…”

Section: Methodsmentioning

confidence: 99%

Electrostatic sheathing of lipoprotein lipase is essential for its movement across capillary endothelial cells

Song¹,

Beigneux²,

Winther³

et al. 2022

Journal of Clinical Investigation

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GPIHBP1, an endothelial cell (EC) protein, captures lipoprotein lipase (LPL) within the interstitial spaces (where it is secreted by myocytes and adipocytes) and transports it across ECs to its site of action in the capillary lumen. GPIHBP1’s 3-fingered LU domain is required for LPL binding, but the function of its acidic domain (AD) has remained unclear. We created mutant mice lacking the AD and found severe hypertriglyceridemia. As expected, the mutant GPIHBP1 retained the capacity to bind LPL. Unexpectedly, however, most of the GPIHBP1 and LPL in the mutant mice was located on the abluminal surface of ECs (explaining the hypertriglyceridemia). The GPIHBP1-bound LPL was trapped on the abluminal surface of ECs by electrostatic interactions between the large basic patch on the surface of LPL and negatively charged heparan sulfate proteoglycans (HSPGs) on the surface of ECs. GPIHBP1 trafficking across ECs in the mutant mice was normalized by disrupting LPL-HSPG electrostatic interactions with either heparin or an AD peptide. Thus, GPIHBP1’s AD plays a crucial function in plasma triglyceride metabolism; it sheathes LPL’s basic patch on the abluminal surface of ECs, thereby preventing LPL-HSPG interactions and freeing GPIHBP1-LPL complexes to move across ECs to the capillary lumen.

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Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1

Cited by 10 publications

References 47 publications

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

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

An upstream enhancer regulates Gpihbp1 expression in a tissue-specific manner

Electrostatic sheathing of lipoprotein lipase is essential for its movement across capillary endothelial cells

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