Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Larsson, Mikael; Vorrsjö, Evelina; Talmud, Philippa J.; Lóokene, Aivar; Olivecrona, Gunilla

doi:10.1074/jbc.m113.495366

Cited by 147 publications

(142 citation statements)

References 72 publications

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“…ApoC-III retards LPL-mediated TRL processing, limiting access of LPL to TRL substrates (33). In transgenic mice that overexpress human apoC-III, TRL processing by the LPL-GPIHBP1 complex is impaired (34), causing hypertriglyceridemia.…”

Section: Resultsmentioning

confidence: 99%

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

Larsson

Allan

Heizer

et al. 2018

Journal of Lipid Research

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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.

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Section: Resultsmentioning

confidence: 99%

“…suggesting that the higher LPL activity in BAT during cold exposure (35,36) outweighs the ability of apoC-III to limit LPL accessibility to triglyceride substrates (33,34). We also examined mice deficient in both apoC-III and GPIHBP1 (Gpihbp1 −/− Apoc3 −/− ).…”

Section: Resultsmentioning

confidence: 99%

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

Larsson

Allan

Heizer

et al. 2018

Journal of Lipid Research

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“…On the other hand, the role of apoC-I on TRLs has solely been examined in vitro and in murine models. apoC-I was found to inhibit the binding of LPL to lipid emulsions, decreasing TG hydrolysis and rendering unbound-LPL more prone to inactivation (41). ApoE knockout mice overexpressing human apoC-I have reduced uptake of 3 H-TG-derived NEFAs from intravenously administered 3 H-VLDL-like particles only in WAT (21).…”

Section: Direct Effect Of Human Apoc-i On In Situ Lpl Activity In 3t3mentioning

confidence: 99%

WAT apoC-I secretion: role in delayed chylomicron clearance in vivo and ex vivo in WAT in obese subjects

Cyr

Wassef

Bissonnette

et al. 2016

Journal of Lipid Research

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The cardiometabolic risk associated with reduced HDL cholesterol (HDL-C) and/or elevated LDL cholesterol (LDL-C) has been well-established, the cardiometabolic risk associated with elevated TG-rich lipoproteins (TRLs) has not. However, elevated concentrations of TRLs have received much interest lately given their association with obesity, insulin resistance, and type 2 diabetes (1, 2). Two recent meta-analyses identified hypertriglyceridemia as a predictor of cardiovascular disease (3, 4). Although controversy exists regarding the independent contribution of fasting hypertriglyceridemia because of its inverse relationship with HDL-C (3, 5), that of postprandial hypertriglyceridemia remains sturdy even after adjustment for HDL-C (5-7). Accordingly, much research has now focused on factors that regulate postprandial TRL clearance.Clearance of postprandial TRLs is highly dependent on white adipose tissue (WAT). A fundamental function of WAT in the postprandial state is the hydrolysis of the TG core of TRLs through the activity of endothelial LPL and the uptake and storage of released NEFAs (8-10). Dysfunctional WAT has reduced metabolic flexibility and is unable to switch promptly from fasting (catabolic) to postprandial (anabolic) state. This leads to delayed TRL clearance, impaired remodeling of circulating lipoproteins, and increased TRL flux to peripheral tissues; thereby increasing cardiometabolic risks (11,12). The underlying mechanisms promoting WAT dysfunction and delayed TRL clearance are not fully understood.

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“…apo-CII is an obligatory activating co-factor of LPL whilst apo-CI and apo-CIII are inhibitors [75].…”

Section: Lipoprotein Lipase Mediated Myocardial Tag Uptakementioning

confidence: 99%

“…TGRLPs bind and stabilise LPL and protect it from angptl-4 inhibition; apo-CI and CIII inhibit this stabilisation [75]. Apo-E inhibits [76] and apo-AV stimulates [77] LPL and plasma TAG clearance.…”

Section: Lipoprotein Lipase Mediated Myocardial Tag Uptakementioning

confidence: 99%

The role of triacylglycerol in cardiac energy provision

Evans

Hui‐Kang

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Triacylglycerols (TAG) constitute the main energy storage resource in mammals, by virtue of their high energy density. This in turn is a function of their highly reduced state and hydrophobicity.Limited water solubility, however, imposes specific requirements for delivery and uptake mechanisms on TAG-utilising tissues, including the heart, as well as intracellular disposition. TAGs constitute potentially the major energy supply for working myocardium, both through bloodborne provision and as intracellular TAG within lipid droplets, but also provide the heart with fatty acids (FA) which the myocardium cannot itself synthesise but are required for glycerolipid derivatives with (non-energetic) functions, including membrane phospholipids and lipid signalling molecules. Furthermore they serve to buffer potentially toxic amphipathic fatty acid derivatives.Intracellular handling and disposition of TAGs and their FA and glycerolipid derivatives similarly requires dedicated mechanisms in view of their hydrophobic character. Dysregulation of utilisation can result in inadequate energy provision, accumulation of TAG and/or esterified species, and these may be responsible for significant cardiac dysfunction in a variety of disease states. This review will focus on the role of TAG in myocardial energy provision, by providing FAs from exogenous and endogenous TAG sources for mitochondrial oxidation and ATP production, and how this can change in disease and impact on cardiac function. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 3Key words:heart; triacylglycerol; very-low-density lipoprotein; VLDL; chylomicron; lipid droplet Highlights: Triacylglycerols are supplied to the myocardium within chylomicrons and VLDL  Heart assimilates triacylglycerol-rich lipoproteins by LPL and receptor-mediated routes  Exogenous triacylglycerol-derived fatty acids enter an intracellular lipid pool  Intracardiac triacylglycerol is an important source of fatty acids for oxidation  Dysregulation of triacylglycerol metabolism is associated with cardiac dysfunction

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Apolipoproteins C-I and C-III Inhibit Lipoprotein Lipase Activity by Displacement of the Enzyme from Lipid Droplets

Cited by 147 publications

References 72 publications

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

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

WAT apoC-I secretion: role in delayed chylomicron clearance in vivo and ex vivo in WAT in obese subjects

The role of triacylglycerol in cardiac energy provision

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