Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

Lafferty, Michael; Bradford, Kira C.; Erie, Dorothy A.; Neher, Saskia B.

doi:10.1074/jbc.m113.497602

Cited by 77 publications

(83 citation statements)

References 49 publications

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“…11 Several apolipoproteins including the apoC family, apoA5, apoE, and angiopoietin-like 4 (Angptl4) are also known to modulate LPL activity and action. 11,[13][14][15][16][17][18] In particular, apoC-III has emerged as a clinically important predictor of hypertriglyceridemia because it inhibits LPL-catalyzed hydrolysis of TRLs 19,20 and attenuates the uptake of TRL remnants by the liver. 21,22 In addition, also the cholesterol ester transfer protein (CETP) has been shown to affect TRL composition and metabolism.…”

Section: Borén Et Al Predictors Of Vldl 1 -Tg Metabolism In Obesity 2219mentioning

confidence: 99%

Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity

Borén¹,

Watts

Adiels³

et al. 2015

ATVB

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Objectives— Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL 1 ) triglycerides. Approach and Results— A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL 1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate ( r =0.44, P <0.01; r =0.45, P <0.01) and fractional catabolism ( r =0.49, P <0.001; r =0.55, P <0.001) of VLDL 1 -triglycerides and VLDL 1 -apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL 1 -triglycerides ( r =0.56, P <0.001) and VLDL 1 -apoB ( r =0.53, P <0.001). Plasma apoC-III concentration was independently and inversely associated with the fractional catabolisms of VLDL 1 -triglycerides ( r =0.48, P <0.001) and VLDL 1 -apoB ( r =0.51, P <0.001). Conclusions— Plasma triglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL 1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity.

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Section: Borén Et Al Predictors Of Vldl 1 -Tg Metabolism In Obesity 2219mentioning

confidence: 99%

Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity

Borén¹,

Watts

Adiels³

et al. 2015

ATVB

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“…Regarding VLDL-TG hydrolysis, we found a significant increase in LPL mRNA during ACI but not during PLA, which could represent a counterregulatory response to reduced FFA availability. Conversely, ANGPTL4, an inhibitor of LPL activity (22) that is regulated by FFA in human skeletal muscle (5), increased during exercise on both study days.…”

Section: Discussionmentioning

confidence: 99%

Kinetics and utilization of lipid sources during acute exercise and acipimox

Nellemann

Søndergaard

Jensen

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Nielsen S. Kinetics and utilization of lipid sources during acute exercise and acipimox. Am J Physiol Endocrinol Metab 307: E199 -E208, 2014. First published June 3, 2014 doi:10.1152/ajpendo.00043.2014.-Overweight is associated with abnormalities of lipid metabolism, many of which are reversed by exercise. We investigated the impact of experimental antilipolysis and acute exercise on lipid kinetics and oxidation from VLDL-TG, plasma FFA, and "residual lipids" in overweight men (n ϭ 8) using VLDL-TG and palmitate tracers in combination with muscle biopsies in a randomized, placebo-controlled design. Participants received placebo or acipimox on each study day (4 h of rest, 90 min of exercise at 50% V O2 max). Exercise suppressed VLDL-TG secretion significantly during placebo but not acipimox (placebo-rest: 64.2 Ϯ 9.4; placebo-exercise: 48.3 Ϯ 8.0; acipimox-rest: 55.2 Ϯ 13.4; acipimoxexercise: 52.0 Ϯ 10.9). Resting oxidation of VLDL-TG FA and FFA was significantly reduced during acipimox compared with placebo, whereas "residual lipid oxidation" increased significantly [VLDL-TG oxidation (placebo: 18 Ϯ 3 kcal/h; acipimox: 11 Ϯ 2 kcal/h), FFA oxidation (placebo: 14 Ϯ 2 kcal/h; acipimox: 4 Ϯ 0.5 kcal/h), and residual lipid oxidation (placebo: 3 Ϯ 5 kcal/h; acipimox: 14 Ϯ 5 kcal/h)]. Additionally, during exercise on both placebo and acipimox, oxidation of VLDL-TG and FFA increased, but the relative contribution to total lipid oxidation diminished, except for FFA, which remained unchanged during acipimox. Residual lipid oxidation increased significantly during exercise in both absolute and relative terms. Changes in selected cellular enzymes and proteins provided no explanations for kinetic changes. In conclusion, suppressed FFA availability blunts the effect of exercise on VLDL-TG secretion and modifies the contribution of lipid sources for oxidation. very low-density lipoprotein; exercise; antilipolysis; lipid oxidation OVERWEIGHT IS ASSOCIATED with proatherogenic abnormalities of lipid metabolism. The alterations reflect reduced insulin suppression of both hepatic very low-density lipoprotein triglyceride (VLDL-TG) secretion and adipose tissue lipolysis, leading to greater plasma triglycerides (TG) and free fatty acid (FFA) concentrations (30). Many of these abnormalities are reversed by physical exercise (21). During low-to moderateintensity exercise, fasting lipid oxidation accounts for ϳ50% of energy expenditure (EE) (25,33,46), and the major sources are plasma FFA, intramyocellular lipids (IML), and VLDL-TG fatty acids (FA). Plasma FFA oxidation (19), measured isotopically (15), increases rapidly during exercise. Conversely, measurements of VLDL-TG oxidation are methodologically challenging (24) and have been calculated mostly from regional A-V concentration differences (19); however, these differences cannot differentiate between tissue oxidation and storage, and IML oxidation has usually been calculated indirectly by subtracting plasma FFA oxidation from total lipid oxidation measured by indirect calorimetry (...

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“…Shan et al (57) have proposed that ANGPTL3 and ANGPTL4 inhibit LPL through different mechanisms and that only ANGPTL4 induces irreversible inactivation of LPL. Others have proposed that ANGPTL4 acts as a noncompetitive inhibitor by forming a reversible complex with LPL (58). Using ITC, addition of nanomolar concentrations of ANGPTL4 to plasma was required to see effects on LPL activity.…”

Section: Figmentioning

confidence: 99%

Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry

Reimund

Kovrov

Olivecrona

et al. 2017

Journal of Lipid Research

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LPL is produced and secreted from parenchymal cells like adipocytes and myocytes for transport to the luminal side of the endothelium via interaction with the glycosylphosphatidylinositol-anchored high density lipoprotein binding protein 1 (GPIHBP1) (8). Several plasma components have been shown to directly or indirectly modulate the activity of LPL. apoC-II and apoA-V increase the activity of LPL, while apoC-I, apoC-III, angiopoietin-like protein (ANGPTL)3, ANGPTL4, and ANGPTL8 decrease the activity (1, 9). The expression of each of these proteins depends on nutritional and hormonal factors, so that lipid uptake in tissues to a large extent is regulated by posttranslational effects on LPL (1, 9). It is possible that the macromolecular environment in plasma itself may be an influence on the interaction of LPL with its ligands. The protein concentration of plasma (80 g/l) has been shown to cause significant crowding effects (10). It is also possible that some plasma regulators of LPL activity have not been identified yet.LPL activity can be measured in vitro by using artificial, usually emulsified, systems of radiolabeled, fluorogenic, or chromogenic substrates, or isolated triglyceride-rich lipoproteins (TRLs). The reaction products are detected at certain time points by chemical quantification or by determination of radioactivity or fluorescence. These methods have been used to unravel important aspects of the action of LPL and also to quantitate the levels of LPL activity in cells and tissues. Only small amounts of LPL activity are normally present in the circulating blood (11). Therefore, intravenous injections of heparin are made to release LPL from its endothelial binding sites. Determination of LPL activity in postheparin plasma, using artificial substrate systems, is considered to give an estimation of the amount of active LPL at the vascular endothelium (12).Lack of a suitable technique for continuous monitoring of triglyceride hydrolysis in plasma has hampered the understanding of the action of LPL under physiological Abstract LPL hydrolyzes triglycerides in plasma lipoproteins. Due to the complex regulation mechanism, it has been difficult to mimic the physiological conditions under which LPL acts in vitro. We demonstrate that isothermal titration calorimetry (ITC), using human plasma as substrate, overcomes several limitations of previously used techniques. The high sensitivity of ITC allows continuous recording of the heat released during hydrolysis. Both initial rates and kinetics for complete hydrolysis of plasma lipids can be studied. The hydrolytic breakdown of plasma triglycerides by LPL at the capillary endothelium is a crucial event that contributes to control of the levels of triglycerides in plasma (1, 2). Many recent studies support the view that an elevated level of triglycerides in plasma is an independent risk factor for development of atherosclerosis (3-5). Therefore, the LPL system is considered to be an interesting target for drug design (6, 7). Education and Research Grant IUT 19-9,...

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Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

Cited by 77 publications

References 49 publications

Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity

Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity

Kinetics and utilization of lipid sources during acute exercise and acipimox

Lipoprotein lipase activity and interactions studied in human plasma by isothermal titration calorimetry

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