Hypertriglyceridemia Associated With Abdominal Obesity
2015; Lippincott Williams & Wilkins; Volume: 35; Issue: 10 Linguagem: Inglês
10.1161/atvbaha.115.306412
ISSN1524-4636
Autores Tópico(s)Diabetes, Cardiovascular Risks, and Lipoproteins
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 35, No. 10Hypertriglyceridemia Associated With Abdominal Obesity Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHypertriglyceridemia Associated With Abdominal ObesityGetting Contributing Factors Into Perspective André C. Carpentier André C. CarpentierAndré C. Carpentier From the Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, Quebec, Canada. Originally published1 Oct 2015https://doi.org/10.1161/ATVBAHA.115.306412Arteriosclerosis, Thrombosis, and Vascular Biology. 2015;35:2076–2078Abdominal obesity is associated with a number of important metabolic and cardiovascular abnormalities, including among others ectopic fat accumulation (including liver steatosis), insulin resistance, low-grade inflammation and increased oxidative stress, impaired glucose homeostasis, hypertriglyceridemia, low high-density lipoprotein cholesterol level, hypertension, and abnormalities of hemostasis, contributing to the increased risk of type 2 diabetes mellitus and cardiovascular diseases (ie, cardiometabolic risk).1 The hypertriglyceridemia associated with this condition involves metabolic abnormalities of all triglyceride-rich lipoproteins (chylomicrons, very-low density lipoproteins [VLDL], and their remnants) caused by a complex interplay between environmental factors, such as food intake and physical activity, and cumulative, multiple gene variants.2 Some factors may predominantly increase triglyceride-rich lipoprotein secretion as, for example, excessive food intake and insulin resistance.3–5 Other factors, such as lipoprotein lipase (LPL), apolipoprotein E, and apolipoprotein A5 polymorphisms, may predominantly affect triglyceride-rich lipoprotein clearance either or both through transfer into less buoyant particles or through direct removal of the particle from the circulation.2 The present view is that hypertriglyceridemia associated with abdominal obesity stems from a combination of enhanced triglyceride-rich lipoprotein secretion with some impairment of clearance.2See accompanying article on page 2218In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Borén et al6 report VLDL1 triglyceride and apolipoprotein B100 kinetics in 46 (37 men and 9 women) middle-aged, insulin-resistant subjects with abdominal obesity and mild hypertriglyceridemia (ie, fasting triglyceride between 1.7 and 4.5 mmol/L) or low high-density lipoprotein cholesterol. This study found VLDL fractional clearance rate to be a more important determinant of plasma triglycerides than VLDL secretion rate in subjects with abdominal obesity and mild dyslipidemia. The authors confirmed that the most important determinant of VLDL triglyceride and apolipoprotein B100 secretion rates was increased liver fat measured by 1H-magnetic resonance spectroscopy, in accordance with previous studies.7 Interestingly, plasma apolipoprotein CIII (apoCIII) level was the strongest predictor of VLDL1 triglyceride and apolipoprotein B100 fractional clearance rate. This finding is also in line with a previous study showing a relatively strong inverse correlation between VLDL fractional clearance rate and VLDL to low-density lipoprotein (LDL) conversion rate and total plasma or VLDL apoCIII levels.8,9 The relatively small influence of apolipoprotein E on VLDL clearance in subjects with abdominal obesity contrasts with the importance of apolipoprotein E for VLDL catabolism in healthy individuals.3,10 The contribution of apoCIII to hypertriglyceridemia in humans was directly demonstrated by the significant reduction of circulating VLDL and chylomicron particles with antisense inhibition of apoCIII in subjects with marked hypertriglyceridemia.11 These changes were observed even in subjects with absence of catalytically active LPL,12 suggesting that the effect of apoCIII on triglyceride-rich lipoprotein metabolism is at least partly independent from LPL-mediated lipolysis. Combined with evidence linking antiatherosclerotic effects of apoCIII loss-of-function mutations from large human cohorts and from animal experiments, the study of Borén et al supports an important role of excess secretion of apoCIII in the cardiometabolic risk.13The absence of relationship between postheparin LPL activity and mass and VLDL clearance in the study by Borén et al6 should be taken as an indication of the poor relationship between heparin-mediated LPL mobilization into the circulation and functional LPL in triglyceride-rich lipoproteins14 and on the endothelial surface of organs that require efficient triglyceride lipolysis from these lipoproteins.15 This is further illustrated by the poor diagnostic reliability of postheparin LPL activity for the diagnosis of genetic functional abnormalities of LPL.16 A large fraction of circulating LPL mass is also inactive, making this assay unreliable to predict function in vivo.17The strengths of the study by Borén et al6 include the application of standard, state-of-the-art stable isotopic methods and modeling used for the determination of VLDL-triglyceride and apolipoprotein B100 kinetics, liver and abdominal fat and plasma apolipoproteins, and LPL mass and activity in a relatively large cohort of subjects with abdominal obesity. The selection criteria and absence of healthy controls may, however, have favored a stronger correlation between apoCIII levels and VLDL1 kinetics compared with other lipoproteins, such as apolipoprotein E given that apoCIII-rich VLDL secretion is increased in hypertriglyceridemic individuals.10 The small number of women is also a limitation given that sex is an important determinant of VLDL metabolism in healthy subjects.3 In addition, there is a marked sexual dichotomy in cardiac and adipose tissue–specific chylomicron fatty acid uptake in subjects with impaired glucose tolerance,18 suggesting that sex may influence the direct clearance pathways of triglyceride-rich lipoproteins. More mechanistic studies are clearly needed on these important sex-related differences in triglyceride metabolism.The study by Borén et al contributes to the remarkable and rapid recent advances in our understanding of the factors leading to hypertriglyceridemia associated with abdominal obesity. This relatively large mechanistic study has provided more support to the important roles of hepatic steatosis and increased apoCIII for the development of hypertriglyceridemia in abdominal obesity (Figure). The precise contribution of total lipoprotein removal versus lipoprotein triglyceride removal by tissues and LPL versus apoCIII-mediated catabolism remains to be defined. Furthermore, the contributing role of disordered metabolism of triglyceride-rich lipoproteins at the end organ level to the dyslipidemia associated with the cardiometabolic risk is still poorly understood in humans. Application of novel therapies using apoCIII inhibition11,12 and LPL gene transfer19 and the recent development of innovative methods able to more directly measure end-organ metabolism of triglyceride-rich lipoproteins20,21 offer outstanding opportunities to bridge these knowledge gaps in the near future.Download figureDownload PowerPointFigure. Factors contributing to hypertriglyceridemia associated with abdominal obesity. According to the study of Borén et al6 in this issue, increased VLDL secretion, impaired VLDL transport in less buoyant lipoproteins, and direct clearance of VLDL particles accounted for ≈20%, 37%, and 9%, respectively, of plasma triglyceride variance in subjects with the cardiometabolic risk. Liver steatosis and increased plasma level of apolipoprotein CIII were the factors most closely related to increased VLDL secretion and impaired clearance, respectively. B-48 indicates apolipoprotein B48; B-100, apolipoprotein B100; C-II, apolipoprotein CII; C-III, apolipoprotein CIII; E, apolipoprotein E; LPL, lipoprotein lipase; TG, triglyceride; and VLDL, very-low density lipoprotein.AcknowledgmentsWarm thanks to Monique Sullivan for editing the text and Anick Turgeon for editing the figure.DisclosuresDr Carpentier received significant grant funding (>10k) from UniQure for studies on Alipogene tiparvovec effect on chylomicron metabolism. He also received modest honorarium (<10k) from UniQure for Advisory Board services.FootnotesCorrespondence to Dr André C. Carpentier, Division of Endocrinology, Faculty of Medicine, University of Sherbrooke, 3001, 12th Ave N, Sherbrooke, Quebec, Canada J1H 5N4. E-mail [email protected]References1. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome.Nature. 2006; 444:881–887. doi: 10.1038/nature05488.CrossrefMedlineGoogle Scholar2. Lewis GF, Xiao C, Hegele RA. 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Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans.Diabetes. 2012; 61:2701–2710. doi: 10.2337/db11-1805.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Zheng J, Jiang M and Xie Y (2021) Influence of uric acid on the correlation between waist circumference and triglyceride glucose index: an analysis from CHARLS, Lipids in Health and Disease, 10.1186/s12944-021-01474-0, 20:1, Online publication date: 1-Dec-2021. Urrunaga-Pastor D, De La Fuente-Carmelino L, Toro-Huamanchumo C, Pérez-Zavala M and Benites-Zapata V (2019) Association between waist circumference and waist-to-height ratio with insulin resistance biomarkers in normal-weight adults working in a private educational institution, Diabetes & Metabolic Syndrome: Clinical Research & Reviews, 10.1016/j.dsx.2019.04.039, 13:3, (2041-2047), Online publication date: 1-May-2019. 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Taskinen M and Borén J (2016) Why Is Apolipoprotein CIII Emerging as a Novel Therapeutic Target to Reduce the Burden of Cardiovascular Disease?, Current Atherosclerosis Reports, 10.1007/s11883-016-0614-1, 18:10, Online publication date: 1-Oct-2016. October 2015Vol 35, Issue 10 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.115.306412PMID: 26399918 Originally publishedOctober 1, 2015 Keywordshypertriglyceridemialipoprotein lipaseapolipoprotein CIIIabdominal obesityhepatic steatosisVLDLPDF download Advertisement
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