GPIHBP1 and Plasma Triglyceride Metabolism

Journal of Lipid Research

et al. 2016

Self Cite

For more than 50 years, it has been known that LPL, a triglyceride hydrolase secreted by myocytes and adipocytes, is crucial for the intravascular processing of triglyceriderich lipoproteins (TRLs) (1-3). For most of that time, it was assumed that LPL was attached to the heparan-sulfate proteoglycans along the lumen of blood vessels (4), but how LPL reached the lumen of blood vessels was a stubborn mystery. Within the past few years, that mystery has been solved (5, 6). Glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1), a GPI-anchored protein of capillary endothelial cells, picks up freshly secreted LPL within the interstitial spaces and shuttles it across endothelial cells to the capillary lumen (7,8). In the absence of GPIHBP1, LPL remains in the interstitial spaces and never reaches the capillary lumen, resulting in an accumulation of plasma TRLs and extremely high plasma triglyceride levels ("chylomicronemia") (8). Recent studies showed that GPIHBP1 (and GPIHBP1-bound LPL) are also crucial for the margination of TRLs along the capillary lumen, allowing triglyceride hydrolysis to proceed (9).GPIHBP1 has two main structural features-an aminoterminal acidic domain and a cysteine-rich three-fingered "LU domain" (7, 10). Recent studies have shown that the Abstract LPL contains two principal domains: an aminoterminal catalytic domain (residues 1-297) and a carboxylterminal domain (residues 298-448) that is important for binding lipids and binding glycosylphosphatidylinositolanchored high density lipoprotein binding protein 1 (GPIHBP1) (an endothelial cell protein that shuttles LPL to the capillary lumen). The LPL sequences required for GPIHBP1 binding have not been examined in detail, but one study suggested that sequences near LPL's carboxyl terminus (residues 403-438) were crucial. Here, we tested the ability of LPLspecific monoclonal antibodies (mAbs) to block the binding of LPL to GPIHBP1. One antibody, 88B8, abolished LPL binding to GPIHBP1. Consistent with those results, antibody 88B8 could not bind to GPIHBP1-bound LPL on cultured cells. Antibody 88B8 bound poorly to LPL proteins with amino acid substitutions that interfered with GPIHBP1 binding (e.g., C418Y, E421K). However, the sequences near LPL's carboxyl terminus (residues 403-438) were not sufficient for 88B8 binding; upstream sequences (residues 298-400) were also required. Additional studies showed that these same sequences are required for LPL binding to GPI-HBP1. In conclusion, we identified an LPL mAb that binds to LPL's GPIHBP1-binding domain. The binding of both antibody 88B8 and GPIHBP1 to LPL depends on large segments of LPL's carboxyl-terminal domain.

Section: Monoclonal Antibodiesmentioning

confidence: 99%

An LPL–specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1

Allan

Journal of Lipid Research

et al. 2016

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“…, heart, skeletal muscle, adipose tissue). LPL is secreted into the interstitial spaces by myocytes and adipocytes but is then shuttled to the capillary lumen by an endothelial transporter, glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1) (Fong et al, 2016). This endothelial cell LPL transporter is also required for the margination of TRLs along capillaries (Goulbourne et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding

Mysling

Kristensen

et al. 2016

eLife

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161

Lipoprotein lipase (LPL) undergoes spontaneous inactivation via global unfolding and this unfolding is prevented by GPIHBP1 (Mysling et al., 2016). We now show: (1) that ANGPTL4 inactivates LPL by catalyzing the unfolding of its hydrolase domain; (2) that binding to GPIHBP1 renders LPL largely refractory to this inhibition; and (3) that both the LU domain and the intrinsically disordered acidic domain of GPIHBP1 are required for this protective effect. Genetic studies have found that a common polymorphic variant in ANGPTL4 results in lower plasma triglyceride levels. We now report: (1) that this ANGPTL4 variant is less efficient in catalyzing the unfolding of LPL; and (2) that its Glu-to-Lys substitution destabilizes its N-terminal α-helix. Our work elucidates the molecular basis for regulation of LPL activity by ANGPTL4, highlights the physiological relevance of the inherent instability of LPL, and sheds light on the molecular defects in a clinically relevant variant of ANGPTL4.DOI: http://dx.doi.org/10.7554/eLife.20958.001

“…GPIHBP1, a glycoprotein of capillary endothelial cells, plays three important functions in plasma triglyceride metabolism (1). First, GPIHBP1 captures lipoprotein lipase (LPL) in the interstitial spaces and transports it to its site of action in the capillary lumen (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…In Gpihbp1 -/-mice, the plasma triglyceride levels on a chow diet are ~4,000 mg/dl (2,3,10). But while high plasma triglyceride levels in Gpihbp1 -/-mice have been well documented (1), it is unclear how these mice respond to metabolic stress, such as that associated with exposure to the cold.…”

Section: Introductionmentioning

confidence: 99%

Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure

Journal of Lipid Research

Allan

Heizer

et al. 2018

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Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1), an endothelial cell protein, binds LPL in the subendothelial spaces and transports it to the capillary lumen. In Gpihbp1−/− mice, LPL remains stranded in the subendothelial spaces, causing hypertriglyceridemia, but how Gpihbp1−/− mice respond to metabolic stress (e.g., cold exposure) has never been studied. In wild-type mice, cold exposure increases LPL-mediated processing of triglyceride-rich lipoproteins (TRLs) in brown adipose tissue (BAT), providing fuel for thermogenesis and leading to lower plasma triglyceride levels. We suspected that defective TRL processing in Gpihbp1−/− mice might impair thermogenesis and blunt the fall in plasma triglyceride levels. Indeed, Gpihbp1−/− mice exhibited cold intolerance, but the effects on plasma triglyceride levels were paradoxical. Rather than falling, the plasma triglyceride levels increased sharply (from ∼4,000 to ∼15,000 mg/dl), likely because fatty acid release by peripheral tissues drives hepatic production of TRLs that cannot be processed. We predicted that the sharp increase in plasma triglyceride levels would not occur in Gpihbp1−/−Angptl4−/− mice, where LPL activity is higher and baseline plasma triglyceride levels are lower. Indeed, the plasma triglyceride levels in Gpihbp1−/−Angptl4−/− mice fell during cold exposure. Metabolic studies revealed increased levels of TRL processing in the BAT of Gpihbp1−/−Angptl4−/− mice.