GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism

Young, Stephen G.; Fong, Loren G.; Beigneux, Anne P.; Allan, Christopher M.; He, Cuiwen; Jiang, Haibo; Nakajima, Katsuyuki; Meiyappan, Muthuraman; Birrane, Gabriel; Ploug, Michael

doi:10.1016/j.cmet.2019.05.023

Cited by 107 publications

(98 citation statements)

References 131 publications

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“…Recent studies implying that freshly secreted LPL is active as a monomer (35), combined with doubts about the physiologic relevance of the homodimer conformation in the crystal structure (31,32,36), prompted us to reconsider mechanisms by which ANGPTL4 inactivates LPL. We found one scenario attractive-that ANGPTLs directly catalyze the unfolding of LPL's hydrolase domain irrespective of any dimer−monomer transition.…”

Section: Significancementioning

confidence: 99%

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism

Kristensen

Leth-Espensen

Mertens

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.

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Section: Significancementioning

confidence: 99%

Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism

Kristensen

Leth-Espensen

Mertens

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…GPIHBP1's acidic and intrinsically disordered domain was not visualized in the crystal structure (11), but was clearly positioned to extend across a very large basic patch on the surface of LPL (spanning both the amino-terminal catalytic domain and the carboxyl-terminal lipid-binding domain) (11). We suspect that electrostatic interactions between GPIHBP1's acidic domain and LPL's basic patch forms a fuzzy complex, which functions to stabilize LPL and block the propensity of LPL's catalytic domain to unfold (2,11).…”

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confidence: 98%

“…Supplementary key words: GPIHBP1 l lipoprotein lipase l chylomicronemia l autoantibodies GPIHBP1 and LPL, obligate partners in plasma triglyceride metabolism GPIHBP1, a glycosylphosphatidylinositol (GPI)-anchored protein of capillary endothelial cells, is a crucial partner for lipoprotein lipase (LPL) in plasma triglyceride metabolism (1,2). GPIHBP1 captures LPL from the subendothelial spaces (where it is secreted by parenchymal cells) and shuttles LPL across endothelial cells to its site of action in the capillary lumen ( Fig.…”

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confidence: 99%

Chylomicronemia from GPIHBP1 autoantibodies

Miyashita

Lutz²,

Hudgins

et al. 2020

Journal of Lipid Research

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Some cases of chylomicronemia are caused by autoantibodies against GPIHBP1, an endothelial cell protein that shuttles lipoprotein lipase (LPL) to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the “GPIHBP1 autoantibody syndrome” and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody–based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in 5 patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.

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“…The lipolytic processing of triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase has been studied at the biochemical level for >60 years (1,2), but until recently it was not possible to image TRL processing or glean insights into the movement of lipoprotein-derived nutrients into tissues. We applied a new method, combining stable isotope labeling of TRLs and nanoscale secondary ion mass spectrometry (NanoSIMS), to visualize the movement of TRL-derived lipids across capillaries and into surrounding parenchymal cells (3,4).…”

mentioning

confidence: 99%