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  • Review Article
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Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia

Nature Reviews Cardiology volume 19, pages 577–592 (2022)Cite this article

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Abstract

Accumulating evidence points to the causal role of triglyceride-rich lipoproteins and their cholesterol-enriched remnants in atherogenesis. Genetic studies in particular have not only revealed a relationship between plasma triglyceride levels and the risk of atherosclerotic cardiovascular disease, but have also identified key proteins responsible for the regulation of triglyceride transport. Kinetic studies in humans using stable isotope tracers have been especially useful in delineating the function of these proteins and revealing the hitherto unappreciated complexity of triglyceride-rich lipoprotein metabolism. Given that triglyceride is an essential energy source for mammals, triglyceride transport is regulated by numerous mechanisms that balance availability with the energy demands of the body. Ongoing investigations are focused on determining the consequences of dysregulation as a result of either dietary imprudence or genetic variation that increases the risk of atherosclerosis and pancreatitis. The identification of molecular control mechanisms involved in triglyceride metabolism has laid the groundwork for a ‘precision-medicine’ approach to therapy. Novel pharmacological agents under development have specific molecular targets within a regulatory framework, and their deployment heralds a new era in lipid-lowering-mediated prevention of disease. In this Review, we outline what is known about the dysregulation of triglyceride transport in human hypertriglyceridaemia.

Key points

  • Triglyceride-rich lipoproteins (TRLs), in particular, their cholesterol-rich remnants, are now considered causal agents for atherogenesis and a suitable target for diet-based and drug-based interventions to prevent coronary heart disease.

  • The optimal level of plasma triglycerides is <1.2 mmol/l; plasma triglyceride levels >1.2 mmol/l are associated with increasing risk of atherosclerosis and pancreatitis (the latter in particular when plasma triglyceride levels are >10 mmol/l).

  • Highly regulated metabolic pathways control the release of TRLs in their tissues of origin (the intestine and liver), lipolysis and remodeling in the bloodstream, and clearance of remnant particles after the core triglycerides have been delivered to their destination is normally rapid and is facilitated by hepatic receptors.

  • Given that current treatments are inadequate in reducing triglycerides to optimal levels, novel treatments under development focus on increasing the efficiency of lipolysis and finding an approach to regulate plasma levels of TRLs and their remnants.

  • Large-scale outcome trials will be required to test the hypothesis that specifically lowering TRLs and remnants can reduce the risk of cardiovascular disease.

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Fig. 1: Regulatory pathways involved in the assembly and secretion of triglyceride-rich lipoproteins.
Fig. 2: Biosynthesis and secretion of VLDL from the liver.
Fig. 3: Regulation of lipolysis and clearance of TRLs.
Fig. 4: Simulation depicting the typical patterns of postprandial accumulation of apoB-100 and apoB-48 across 24 h.
Fig. 5: Role of TRLs and their remnants in atherogenesis.

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References

  1. Ginsberg, H. N. et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society. Eur. Heart J. 42, 4791–4806 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Emerging Risk Factors, C. et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302, 1993–2000 (2009).

    Article  Google Scholar 

  3. Chapman, M. J. et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart J. 32, 1345–1361 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Austin, M. A. Plasma triglyceride and coronary heart disease. Arterioscler. Thromb. 11, 2–14 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Tall, A. R. HDL in morbidity and mortality: a 40+ year perspective. Clin. Chem. 67, 19–23 (2021).

    Article  PubMed  Google Scholar 

  6. Olofsson, S. O. & Boren, J. Apolipoprotein B: a clinically important apolipoprotein which assembles atherogenic lipoproteins and promotes the development of atherosclerosis. J. Intern. Med. 258, 395–410 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Boren, J. et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur. Heart J. 41, 2313–2330 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Davidson, N. O. & Shelness, G. S. APOLIPOPROTEIN B: mRNA editing, lipoprotein assembly, and presecretory degradation. Annu. Rev. Nutr. 20, 169–193 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Anant, S. & Davidson, N. O. Molecular mechanisms of apolipoprotein B mRNA editing. Curr. Opin. Lipidol. 12, 159–165 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Wang, A. B., Liu, D. P. & Liang, C. C. Regulation of human apolipoprotein B gene expression at multiple levels. Exp. Cell Res. 290, 1–12 (2003).

    Article  CAS  PubMed  Google Scholar 

  11. Chan, L. et al. From editosome to proteasome. Recent. Prog. Horm. Res. 55, 93–125 (2000). discussion 126.

    CAS  PubMed  Google Scholar 

  12. Barrows, B. R. & Parks, E. J. Contributions of different fatty acid sources to very low-density lipoprotein-triacylglycerol in the fasted and fed states. J. Clin. Endocrinol. Metab. 91, 1446–1452 (2006).

    Article  CAS  PubMed  Google Scholar 

  13. Donnelly, K. L. et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Invest. 115, 1343–1351 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Smith, G. I. et al. Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease. J. Clin. Invest. 130, 1453–1460 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Browning, J. D. & Horton, J. D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114, 147–152 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Koo, S. H., Dutcher, A. K. & Towle, H. C. Glucose and insulin function through two distinct transcription factors to stimulate expression of lipogenic enzyme genes in liver. J. Biol. Chem. 276, 9437–9445 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Deprince, A., Haas, J. T. & Staels, B. Dysregulated lipid metabolism links NAFLD to cardiovascular disease. Mol. Metab. 42, 101092 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Fisher, E. A. & Ginsberg, H. N. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J. Biol. Chem. 277, 17377–17380 (2002).

    Article  CAS  PubMed  Google Scholar 

  19. Boren, J. et al. The assembly and secretion of ApoB 100-containing lipoproteins in Hep G2 cells. ApoB 100 is cotranslationally integrated into lipoproteins. J. Biol. Chem. 267, 9858–9867 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Gordon, D. A., Jamil, H., Gregg, R. E., Olofsson, S. O. & Boren, J. Inhibition of the microsomal triglyceride transfer protein blocks the first step of apolipoprotein B lipoprotein assembly but not the addition of bulk core lipids in the second step. J. Biol. Chem. 271, 33047–33053 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Olofsson, S. O. & Boren, J. Apolipoprotein B secretory regulation by degradation. Arterioscler. Thromb. Vasc. Biol. 32, 1334–1338 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Ginsberg, H. N. & Fisher, E. A. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J. Lipid Res. 50, S162–S166 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Stillemark, P. et al. The assembly and secretion of apolipoprotein B-48-containing very low density lipoproteins in McA-RH7777 cells. J. Biol. Chem. 275, 10506–10513 (2000).

    Article  CAS  PubMed  Google Scholar 

  24. Wang, X. et al. Receptor-mediated ER export of lipoproteins controls lipid homeostasis in mice and humans. Cell Metab. 33, 350–-366 e357 (2021).

    Article  CAS  PubMed  Google Scholar 

  25. Rustaeus, S., Stillemark, P., Lindberg, K., Gordon, D. & Olofsson, S. O. The microsomal triglyceride transfer protein catalyzes the post-translational assembly of apolipoprotein B-100 very low density lipoprotein in McA-RH7777 cells. J. Biol. Chem. 273, 5196–5203 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Adiels, M. et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 49, 755–765 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Boren, J. et al. Influence of triacylglycerol biosynthesis rate on the assembly of apoB-100-containing lipoproteins in Hep G2 cells. Arterioscler. Thromb. 13, 1743–1754 (1993).

    Article  CAS  PubMed  Google Scholar 

  28. Packard, C. J., Boren, J. & Taskinen, M. R. Causes and consequences of hypertriglyceridemia. Front. Endocrinol. 11, 252 (2020).

    Article  Google Scholar 

  29. Malmstrom, R. et al. Metabolic basis of hypotriglyceridemic effects of insulin in normal men. Arterioscler. Thromb. Vasc. Biol. 17, 1454–1464 (1997).

    Article  CAS  PubMed  Google Scholar 

  30. Lewis, G. F. et al. VLDL production is decreased to a similar extent by acute portal vs. peripheral venous insulin. Am. J. Physiol. 267, E566–E572 (1994).

    CAS  PubMed  Google Scholar 

  31. Cummings, M. H. et al. Acute hyperinsulinemia decreases the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in NIDDM. Diabetes 44, 1059–1065 (1995).

    Article  CAS  PubMed  Google Scholar 

  32. Malmstrom, R. et al. Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects. Diabetes 47, 779–787 (1998).

    Article  CAS  PubMed  Google Scholar 

  33. Lewis, G. F., Uffelman, K. D., Szeto, L. W., Weller, B. & Steiner, G. Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J. Clin. Invest. 95, 158–166 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Adiels, M. et al. Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance. Diabetologia 50, 2356–2365 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Pavlic, M., Xiao, C., Szeto, L., Patterson, B. W. & Lewis, G. F. Insulin acutely inhibits intestinal lipoprotein secretion in humans in part by suppressing plasma free fatty acids. Diabetes 59, 580–587 (2010).

    Article  CAS  PubMed  Google Scholar 

  36. Loomba, R., Friedman, S. L. & Shulman, G. I. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 184, 2537–2564 (2021).

    Article  CAS  PubMed  Google Scholar 

  37. Xiao, C., Pavlic, M., Szeto, L., Patterson, B. W. & Lewis, G. F. Effects of acute hyperglucagonemia on hepatic and intestinal lipoprotein production and clearance in healthy humans. Diabetes 60, 383–390 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nielsen, S. & Karpe, F. Determinants of VLDL-triglycerides production. Curr. Opin. Lipidol. 23, 321–326 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Palmisano, B. T., Zhu, L. & Stafford, J. M. Role of estrogens in the regulation of liver lipid metabolism. Adv. Exp. Med. Biol. 1043, 227–256 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Fielding, B. A. et al. Ethanol with a mixed meal increases postprandial triacylglycerol but decreases postprandial non-esterified fatty acid concentrations. Br. J. Nutr. 83, 597–604 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Brinton, E. A. Effects of ethanol intake on lipoproteins and atherosclerosis. Curr. Opin. Lipidol. 21, 346–351 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Taskinen, M. R. et al. Alcohol-induced changes in serum lipoproteins and in their metabolism. Am. Heart J. 113, 458–464 (1987).

    Article  CAS  PubMed  Google Scholar 

  43. Prinsen, B. H. et al. Endogenous cholesterol synthesis is associated with VLDL-2 apoB-100 production in healthy humans. J. Lipid Res. 44, 1341–1348 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Gaw, A. et al. Overproduction of small very low density lipoproteins (Sf 20-60) in moderate hypercholesterolemia: relationships between apolipoprotein B kinetics and plasma lipoproteins. J. Lipid Res. 36, 158–171 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. James, R. W. et al. Apolipoprotein B metabolism in homozygous familial hypercholesterolemia. J. Lipid Res. 30, 159–169 (1989).

    Article  CAS  PubMed  Google Scholar 

  46. Xiao, C., Stahel, P. & Lewis, G. F. Regulation of chylomicron secretion: focus on post-assembly mechanisms. Cell Mol. Gastroenterol. Hepatol. 7, 487–501 (2019).

    Article  PubMed  Google Scholar 

  47. Hussain, M. M., Fatma, S., Pan, X. & Iqbal, J. Intestinal lipoprotein assembly. Curr. Opin. Lipidol. 16, 281–285 (2005).

    Article  CAS  PubMed  Google Scholar 

  48. Levy, E., Beaulieu, J. F. & Spahis, S. From congenital disorders of fat malabsorption to understanding intra-enterocyte mechanisms behind chylomicron assembly and secretion. Front. Physiol. 12, 629222 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Stahel, P., Xiao, C., Nahmias, A. & Lewis, G. F. Role of the gut in diabetic dyslipidemia. Front. Endocrinol. 11, 116 (2020).

    Article  Google Scholar 

  50. Giammanco, A., Cefalu, A. B., Noto, D. & Averna, M. R. The pathophysiology of intestinal lipoprotein production. Front. Physiol. 6, 61 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cartwright, I. J., Plonne, D. & Higgins, J. A. Intracellular events in the assembly of chylomicrons in rabbit enterocytes. J. Lipid Res. 41, 1728–1739 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. Xiao, C., Stahel, P., Nahmias, A. & Lewis, G. F. Emerging role of lymphatics in the regulation of intestinal lipid mobilization. Front. Physiol. 10, 1604 (2019).

    Article  PubMed  Google Scholar 

  53. Lambert, J. E. & Parks, E. J. Postprandial metabolism of meal triglyceride in humans. Biochim. Biophys. Acta 1821, 721–726 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Mattes, R. D. Oral fat exposure increases the first phase triacylglycerol concentration due to release of stored lipid in humans. J. Nutr. 132, 3656–3662 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Chavez-Jauregui, R. N., Mattes, R. D. & Parks, E. J. Dynamics of fat absorption and effect of sham feeding on postprandial lipema. Gastroenterology 139, 1538–1548 (2010).

    Article  PubMed  Google Scholar 

  56. Khan, N. A. & Besnard, P. Oro-sensory perception of dietary lipids: new insights into the fat taste transduction. Biochim. Biophys. Acta 1791, 149–155 (2009).

    Article  CAS  PubMed  Google Scholar 

  57. Mattes, R. D. Brief oral stimulation, but especially oral fat exposure, elevates serum triglycerides in humans. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G365–G371 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Robertson, M. D. et al. Mobilisation of enterocyte fat stores by oral glucose in humans. Gut 52, 834–839 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Xiao, C. et al. Oral glucose mobilizes triglyceride stores from the human intestine. Cell Mol. Gastroenterol. Hepatol. 7, 313–337 (2019).

    Article  PubMed  Google Scholar 

  60. Bjornson, E. et al. Investigation of human apoB48 metabolism using a new, integrated non-steady-state model of apoB48 and apoB100 kinetics. J. Intern. Med. 285, 562–577 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bjornson, E. et al. Apolipoprotein B48 metabolism in chylomicrons and very low-density lipoproteins and its role in triglyceride transport in normo- and hypertriglyceridemic human subjects. J. Intern. Med. 288, 422–438 (2020).

    Article  CAS  PubMed  Google Scholar 

  62. Xiao, C., Stahel, P., Carreiro, A. L., Buhman, K. K. & Lewis, G. F. Recent advances in triacylglycerol mobilization by the gut. Trends Endocrinol. Metab. 29, 151–163 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Nahmias, A., Stahel, P., Tian, L., Xiao, C. & Lewis, G. F. GLP-1 (glucagon-like peptide-1) is physiologically relevant for chylomicron secretion beyond its known pharmacological role. Arterioscler. Thromb. Vasc. Biol. 41, 1893–1900 (2021).

    Article  CAS  PubMed  Google Scholar 

  64. Stahel, P., Xiao, C., Nahmias, A., Tian, L. & Lewis, G. F. Multi-organ coordination of lipoprotein secretion by hormones, nutrients and neural networks. Endocr. Rev. 42, 815–838 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Taskinen, M. R. et al. Effects of liraglutide on the metabolism of triglyceride-rich lipoproteins in type 2 diabetes. Diabetes Obes. Metab. 23, 1191–1201 (2021).

    Article  CAS  PubMed  Google Scholar 

  66. Stemmer, K., Finan, B., DiMarchi, R. D., Tschop, M. H. & Muller, T. D. Insights into incretin-based therapies for treatment of diabetic dyslipidemia. Adv. Drug. Deliv. Rev. 159, 34–53 (2020).

    Article  CAS  PubMed  Google Scholar 

  67. Hein, G. J., Baker, C., Hsieh, J., Farr, S. & Adeli, K. GLP-1 and GLP-2 as yin and yang of intestinal lipoprotein production: evidence for predominance of GLP-2-stimulated postprandial lipemia in normal and insulin-resistant states. Diabetes 62, 373–381 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Verges, B. et al. Liraglutide reduces postprandial hyperlipidemia by increasing ApoB48 (apolipoprotein B48) catabolism and by reducing apob48 production in patients with type 2 diabetes mellitus. Arterioscler. Thromb. Vasc. Biol. 38, 2198–2206 (2018).

    Article  CAS  PubMed  Google Scholar 

  69. Berberich, A. J. & Hegele, R. A. Lipid effects of glucagon-like peptide 1 receptor analogs. Curr. Opin. Lipidol. 32, 191–199 (2021).

    Article  CAS  PubMed  Google Scholar 

  70. Julve, J., Martin-Campos, J. M., Escola-Gil, J. C. & Blanco-Vaca, F. Chylomicrons: advances in biology, pathology, laboratory testing, and therapeutics. Clin. Chim. Acta 455, 134–148 (2016).

    Article  CAS  PubMed  Google Scholar 

  71. Lee, J. & Hegele, R. A. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J. Inherit. Metab. Dis. 37, 333–339 (2014).

    Article  CAS  PubMed  Google Scholar 

  72. Paquette, M., Dufour, R., Hegele, R. A. & Baass, A. A tale of 2 cousins: an atypical and a typical case of abetalipoproteinemia. J. Clin. Lipidol. 10, 1030–1034 (2016).

    Article  PubMed  Google Scholar 

  73. Ginsberg, H. N. ApoB SURFs a ride from the ER to the Golgi. Cell Metab. 33, 231–233 (2021).

    Article  CAS  PubMed  Google Scholar 

  74. Strong, A. & Rader, D. J. Sortilin as a regulator of lipoprotein metabolism. Curr. Atheroscler. Rep. 14, 211–218 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wilson, D. E. et al. Phenotypic expression of heterozygous lipoprotein lipase deficiency in the extended pedigree of a proband homozygous for a missense mutation. J. Clin. Invest. 86, 735–750 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Gilham, D. et al. Inhibitors of hepatic microsomal triacylglycerol hydrolase decrease very low density lipoprotein secretion. Faseb J. 17, 1685–1687 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Dolinsky, V. W., Gilham, D., Alam, M., Vance, D. E. & Lehner, R. Triacylglycerol hydrolase: role in intracellular lipid metabolism. Cell Mol. Life Sci. 61, 1633–1651 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Boren, J. et al. Effects of TM6SF2 E167K on hepatic lipid and very low-density lipoprotein metabolism in humans. JCI Insight 5, e144079 (2020).

    Article  PubMed Central  Google Scholar 

  79. Boren, J. et al. Effects of PNPLA3 I148M on hepatic lipid and very low-density lipoprotein metabolism in humans. J. Intern. Med. 291, 218–223 (2022).

    Article  CAS  PubMed  Google Scholar 

  80. Havel, R. J. & Gordon, R. S. Jr. Idiopathic hyperlipemia: metabolic studies in an affected family. J. Clin. Invest. 39, 1777–1790 (1960).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kersten, S. Physiological regulation of lipoprotein lipase. Biochim. Biophys. Acta 1841, 919–933 (2014).

    Article  CAS  PubMed  Google Scholar 

  82. Semenkovich, C. F., Wims, M., Noe, L., Etienne, J. & Chan, L. Insulin regulation of lipoprotein lipase activity in 3T3-L1 adipocytes is mediated at posttranscriptional and posttranslational levels. J. Biol. Chem. 264, 9030–9038 (1989).

    Article  CAS  PubMed  Google Scholar 

  83. Taskinen, M. R. & Nikkila, E. A. Lipoprotein lipase activity of adipose tissue and skeletal muscle in insulin-deficient human diabetes. Relation to high-density and very-low-density lipoproteins and response to treatment. Diabetologia 17, 351–356 (1979).

    Article  CAS  PubMed  Google Scholar 

  84. Wang, H. & Eckel, R. H. Lipoprotein lipase: from gene to obesity. Am. J. Physiol. Endocrinol. Metab. 297, E271–E288 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Kirchgessner, T. G. et al. Genetic and developmental regulation of the lipoprotein lipase gene: loci both distal and proximal to the lipoprotein lipase structural gene control enzyme expression. J. Biol. Chem. 264, 1473–1482 (1989).

    Article  CAS  PubMed  Google Scholar 

  86. Wu, S. A., Kersten, S. & Qi, L. Lipoprotein lipase and its regulators: an unfolding story. Trends Endocrinol. Metab. 32, 48–61 (2021).

    Article  CAS  PubMed  Google Scholar 

  87. Young, S. G. et al. GPIHBP1 and lipoprotein lipase, partners in plasma triglyceride metabolism. Cell Metab. 30, 51–65 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Ruppert, P. M. M. & Kersten, S. A lipase fusion feasts on fat. J. Biol. Chem. 295, 2913–2914 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Beigneux, A. P. et al. Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 5, 279–291 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Goldberg, I. J. et al. Lipolytic enzymes and free fatty acids at the endothelial interface. Atherosclerosis 329, 1–8 (2021).

    Article  CAS  PubMed  Google Scholar 

  91. Rabacchi, C. et al. Clinical and genetic features of 3 patients with familial chylomicronemia due to mutations in GPIHBP1 gene. J. Clin. Lipidol. 10, 915–921.e914 (2016).

    Article  PubMed  Google Scholar 

  92. Paquette, M., Hegele, R. A., Pare, G. & Baass, A. A novel mutation in GPIHBP1 causes familial chylomicronemia syndrome. J. Clin. Lipidol. 12, 506–510 (2018).

    Article  PubMed  Google Scholar 

  93. Dron, J. S. & Hegele, R. A. Genetics of hypertriglyceridemia. Front. Endocrinol. 11, 455 (2020).

    Article  Google Scholar 

  94. Wolska, A., Reimund, M. & Remaley, A. T. Apolipoprotein C-II: the re-emergence of a forgotten factor. Curr. Opin. Lipidol. 31, 147–153 (2020).

    Article  CAS  PubMed  Google Scholar 

  95. Dai, W., Zhang, Z., Yao, C. & Zhao, S. Emerging evidences for the opposite role of apolipoprotein C3 and apolipoprotein A5 in lipid metabolism and coronary artery disease. Lipids Health Dis. 18, 220 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Kersten, S. Long-lost friend is back in the game. J. Lipid Res. 62, 100072 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Olivecrona, G. & Beisiegel, U. Lipid binding of apolipoprotein CII is required for stimulation of lipoprotein lipase activity against apolipoprotein CII-deficient chylomicrons. Arterioscler. Thromb. Vasc. Biol. 17, 1545–1549 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Jong, M. C., Hofker, M. H. & Havekes, L. M. Role of ApoCs in lipoprotein metabolism: functional differences between ApoC1, ApoC2, and ApoC3. Arterioscler. Thromb. Vasc. Biol. 19, 472–484 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Wolska, A. et al. Apolipoprotein C-II: new findings related to genetics, biochemistry, and role in triglyceride metabolism. Atherosclerosis 267, 49–60 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Reimund, M. et al. Apolipoprotein C-II mimetic peptide is an efficient activator of lipoprotein lipase in human plasma as studied by a calorimetric approach. Biochem. Biophys. Res. Commun. 519, 67–72 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Wolska, A. et al. A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides. Sci. Transl. Med. 12, eaaw7905 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Chen, Y. Q. et al. ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. J. Lipid Res. 62, 100068 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Reeskamp, L. F., Tromp, T. R. & Stroes, E. S. G. The next generation of triglyceride-lowering drugs: will reducing apolipoprotein C-III or angiopoietin like protein 3 reduce cardiovascular disease? Curr. Opin. Lipidol. 31, 140–146 (2020).

    Article  CAS  PubMed  Google Scholar 

  104. Boren, J., Packard, C. J. & Taskinen, M. R. The roles of ApoC-III on the metabolism of triglyceride-rich lipoproteins in humans. Front. Endocrinol. 11, 474 (2020).

    Article  Google Scholar 

  105. Jorgensen, A. B., Frikke-Schmidt, R., Nordestgaard, B. G. & Tybjaerg-Hansen, A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371, 32–41 (2014).

    Article  PubMed  CAS  Google Scholar 

  106. Tg et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med. 371, 22–31 (2014).

    Article  CAS  Google Scholar 

  107. Gaudet, D. et al. Targeting APOC3 in the familial chylomicronemia syndrome. N. Engl. J. Med. 371, 2200–2206 (2014).

    Article  PubMed  CAS  Google Scholar 

  108. Liu, H. et al. Characterization of recombinant wild type and site-directed mutations of apolipoprotein C-III: lipid binding, displacement of ApoE, and inhibition of lipoprotein lipase. Biochemistry 39, 9201–9212 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Sparks, J. D. & Dong, H. H. FoxO1 and hepatic lipid metabolism. Curr. Opin. Lipidol. 20, 217–226 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Taskinen, M. R. & Boren, J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 239, 483–495 (2015).

    Article  CAS  PubMed  Google Scholar 

  111. Jackson, K. G., Wolstencroft, E. J., Bateman, P. A., Yaqoob, P. & Williams, C. M. Greater enrichment of triacylglycerol-rich lipoproteins with apolipoproteins E and C-III after meals rich in saturated fatty acids than after meals rich in unsaturated fatty acids. Am. J. Clin. Nutr. 81, 25–34 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Faghihnia, N., Mangravite, L. M., Chiu, S., Bergeron, N. & Krauss, R. M. Effects of dietary saturated fat on LDL subclasses and apolipoprotein CIII in men. Eur. J. Clin. Nutr. 66, 1229–1233 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Pieke, B. et al. Treatment of hypertriglyceridemia by two diets rich either in unsaturated fatty acids or in carbohydrates: effects on lipoprotein subclasses, lipolytic enzymes, lipid transfer proteins, insulin and leptin. Int. J. Obes. Relat. Metab. Disord. 24, 1286–1296 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. Hiukka, A. et al. Alterations of lipids and apolipoprotein CIII in very low density lipoprotein subspecies in type 2 diabetes. Diabetologia 48, 1207–1215 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. Kanter, J. E. et al. Increased apolipoprotein C3 drives cardiovascular risk in type 1 diabetes. J. Clin. Invest. 129, 4165–4179 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Basu, A. et al. Apolipoprotein-defined lipoprotein subclasses, serum apolipoproteins, and carotid intima-media thickness in T1D. J. Lipid Res. 59, 872–883 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Valladolid-Acebes, I., Berggren, P. O. & Juntti-Berggren, L. Apolipoprotein CIII Is an important piece in the type-1 diabetes jigsaw puzzle. Int. J. Mol. Sci. 22, 932 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Adiels, M. et al. Role of apolipoprotein C-III overproduction in diabetic dyslipidaemia. Diabetes Obes. Metab. 21, 1861–1870 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Jansson Sigfrids, F. et al. Remnant cholesterol predicts progression of diabetic nephropathy and retinopathy in type 1 diabetes. J. Intern. Med. 290, 632–645 (2021).

    Article  CAS  PubMed  Google Scholar 

  120. Ginsberg, H. N. & Reyes-Soffer, G. Is APOC3 the driver of cardiovascular disease in people with type I diabetes mellitus? J. Clin. Invest. 129, 4074–4076 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  121. Kersten, S. New insights into angiopoietin-like proteins in lipid metabolism and cardiovascular disease risk. Curr. Opin. Lipidol. 30, 205–211 (2019).

    Article  CAS  PubMed  Google Scholar 

  122. Koishi, R. et al. Angptl3 regulates lipid metabolism in mice. Nat. Genet. 30, 151–157 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Kersten, S. Angiopoietin-like 3 in lipoprotein metabolism. Nat. Rev. Endocrinol. 13, 731–739 (2017).

    Article  CAS  PubMed  Google Scholar 

  124. Nidhina Haridas, P. A. et al. Regulation of angiopoietin-like proteins (ANGPTLs) 3 and 8 by insulin. J. Clin. Endocrinol. Metab. 100, E1299–E1307 (2015).

    Article  CAS  PubMed  Google Scholar 

  125. Shimamura, M. et al. Angiopoietin-like protein3 regulates plasma HDL cholesterol through suppression of endothelial lipase. Arterioscler. Thromb. Vasc. Biol. 27, 366–372 (2007).

    Article  CAS  PubMed  Google Scholar 

  126. Musunuru, K. et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 363, 2220–2227 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Romeo, S. et al. Rare loss-of-function mutations in ANGPTL family members contribute to plasma triglyceride levels in humans. J. Clin. Invest. 119, 70–79 (2009).

    CAS  PubMed  Google Scholar 

  128. Willer, C. J. et al. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nat. Genet. 40, 161–169 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Arca, M., Minicocci, I. & Maranghi, M. The angiopoietin-like protein 3: a hepatokine with expanding role in metabolism. Curr. Opin. Lipidol. 24, 313–320 (2013).

    Article  CAS  PubMed  Google Scholar 

  130. Stitziel, N. O. et al. ANGPTL3 deficiency and protection against coronary artery disease. J. Am. Coll. Cardiol. 69, 2054–2063 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dewey, F. E. et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377, 211–221 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Gaudet, D. et al. Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. Eur. Heart J. 41, 3936–3945 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Romeo, S. et al. Population-based resequencing of ANGPTL4 uncovers variations that reduce triglycerides and increase HDL. Nat. Genet. 39, 513–516 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ruppert, P. M. M. et al. Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue. Mol. Metab. 40, 101033 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Bini, S. et al. The interplay between angiopoietin-like proteins and adipose tissue: another piece of the relationship between adiposopathy and cardiometabolic diseases? Int. J. Mol. Sci. 22, 742 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  136. Dewey, F. E. et al. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N. Engl. J. Med. 374, 1123–1133 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Liu, D. J. et al. Exome-wide association study of plasma lipids in >300,000 individuals. Nat. Genet. 49, 1758–1766 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Cooper, A. D. Hepatic uptake of chylomicron remnants. J. Lipid Res. 38, 2173–2192 (1997).

    Article  CAS  PubMed  Google Scholar 

  139. Boren, J. et al. Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. J. Clin. Invest. 101, 1084–1093 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Goldstein, J. L. & Brown, M. S. The LDL receptor. Arterioscler. Thromb. Vasc. Biol. 29, 431–438 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lagace, T. A. PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells. Curr. Opin. Lipidol. 25, 387–393 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Chan, D. C. et al. Comparative effects of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition and statins on postprandial triglyceride-rich lipoprotein metabolism. Arterioscler. Thromb. Vasc. Biol. 38, 1644–1655 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Vallejo-Vaz, A. J., Corral, P., Schreier, L. & Ray, K. K. Triglycerides and residual risk. Curr. Opin. Endocrinol. Diabetes Obes. 27, 95–103 (2020).

    Article  CAS  PubMed  Google Scholar 

  144. Taskinen, M. R. et al. Effects of evolocumab on the postprandial kinetics of apo (apolipoprotein) B100- and B48-containing lipoproteins in subjects with type 2 diabetes. Arterioscler. Thromb. Vasc. Biol. 41, 962–975 (2021).

    Article  CAS  PubMed  Google Scholar 

  145. Klop, B. et al. Daytime triglyceride variability in men and women with different levels of triglyceridemia. Clin. Chim. Acta 412, 2183–2189 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Ceriello, A. et al. Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation 106, 1211–1218 (2002).

    Article  PubMed  Google Scholar 

  147. Fard, A. et al. Acute elevations of plasma asymmetric dimethylarginine and impaired endothelial function in response to a high-fat meal in patients with type 2 diabetes. Arterioscler. Thromb. Vasc. Biol. 20, 2039–2044 (2000).

    Article  CAS  PubMed  Google Scholar 

  148. Taskinen, M. R. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 46, 733–749 (2003).

    Article  PubMed  Google Scholar 

  149. Esan, O. & Wierzbicki, A. S. Triglycerides and cardiovascular disease. Curr. Opin. Cardiol. 36, 469–477 (2021).

    Article  PubMed  Google Scholar 

  150. Cohn, J. S. et al. Contribution of apoB-48 and apoB-100 triglyceride-rich lipoproteins (TRL) to postprandial increases in the plasma concentration of TRL triglycerides and retinyl esters. J. Lipid Res. 34, 2033–2040 (1993).

    Article  CAS  PubMed  Google Scholar 

  151. Karpe, F., Bell, M., Bjorkegren, J. & Hamsten, A. Quantification of postprandial triglyceride-rich lipoproteins in healthy men by retinyl ester labeling and simultaneous measurement of apolipoproteins B-48 and B-100. Arterioscler. Thromb. Vasc. Biol. 15, 199–207 (1995).

    Article  CAS  PubMed  Google Scholar 

  152. Schneeman, B. O., Kotite, L., Todd, K. M. & Havel, R. J. Relationships between the responses of triglyceride-rich lipoproteins in blood plasma containing apolipoproteins B-48 and B-100 to a fat-containing meal in normolipidemic humans. Proc. Natl Acad. Sci. USA 90, 2069–2073 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Hiukka, A. et al. Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus. Diabetologia 50, 2067–2075 (2007).

    Article  CAS  PubMed  Google Scholar 

  154. Adiels, M. et al. Postprandial accumulation of chylomicrons and chylomicron remnants is determined by the clearance capacity. Atherosclerosis 222, 222–228 (2012).

    Article  CAS  PubMed  Google Scholar 

  155. Peterson, J. et al. Fatty acid control of lipoprotein lipase: a link between energy metabolism and lipid transport. Proc. Natl Acad. Sci. USA 87, 909–913 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Miles, J. M. et al. Systemic and forearm triglyceride metabolism: fate of lipoprotein lipase-generated glycerol and free fatty acids. Diabetes 53, 521–527 (2004).

    Article  CAS  PubMed  Google Scholar 

  157. Vallejo-Vaz, A. J. et al. Triglyceride-rich lipoprotein cholesterol and risk of cardiovascular events among patients receiving statin therapy in the TNT trial. Circulation 138, 770–781 (2018).

    Article  CAS  PubMed  Google Scholar 

  158. Boren, J., Matikainen, N., Adiels, M. & Taskinen, M. R. Postprandial hypertriglyceridemia as a coronary risk factor. Clin. Chim. Acta 431, 131–142 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Skalen, K. et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 417, 750–754 (2002).

    Article  CAS  PubMed  Google Scholar 

  160. Boren, J. et al. Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J. Clin. Invest. 101, 2658–2664 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Flood, C. et al. Identification of the proteoglycan binding site in apolipoprotein B48. J. Biol. Chem. 277, 32228–32233 (2002).

    Article  CAS  PubMed  Google Scholar 

  162. Salinas, C. A. A. & Chapman, M. J. Remnant lipoproteins: are they equal to or more atherogenic than LDL? Curr. Opin. Lipidol. 31, 132–139 (2020).

    Article  CAS  PubMed  Google Scholar 

  163. Schwartz, E. A. & Reaven, P. D. Lipolysis of triglyceride-rich lipoproteins, vascular inflammation, and atherosclerosis. Biochim. Biophys. Acta 1821, 858–866 (2012).

    Article  CAS  PubMed  Google Scholar 

  164. Cabodevilla, A. G. et al. Eruptive xanthoma model reveals endothelial cells internalize and metabolize chylomicrons, leading to extravascular triglyceride accumulation. J. Clin. Invest. 131, e145800 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  165. Fischer, A. W. et al. Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation. Cell Metab. 33, 547–564.e7 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Moreton, J. R. Physical state of lipids and foreign substances producing atherosclerosis. Science 107, 371–373 (1948).

    Article  CAS  PubMed  Google Scholar 

  167. Zilversmit, D. B. Atherogenesis: a postprandial phenomenon. Circulation 60, 473–485 (1979).

    Article  CAS  PubMed  Google Scholar 

  168. Baass, A., Paquette, M., Bernard, S. & Hegele, R. A. Familial chylomicronemia syndrome: an under-recognized cause of severe hypertriglyceridaemia. J. Intern. Med. 287, 340–348 (2020).

    Article  CAS  PubMed  Google Scholar 

  169. Goldberg, R. B. & Chait, A. A comprehensive update on the chylomicronemia syndrome. Front. Endocrinol. 11, 593931 (2020).

    Article  Google Scholar 

  170. D’Erasmo, L. et al. Spectrum of mutations and long-term clinical outcomes in genetic chylomicronemia syndromes. Arterioscler. Thromb. Vasc. Biol. 39, 2531–2541 (2019).

    Article  PubMed  CAS  Google Scholar 

  171. Hegele, R. A. et al. Clinical and biochemical features of different molecular etiologies of familial chylomicronemia. J. Clin. Lipidol. 12, 920–927.e4 (2018).

    Article  PubMed  Google Scholar 

  172. Dron, J. S. et al. Severe hypertriglyceridemia is primarily polygenic. J. Clin. Lipidol. 13, 80–88 (2019).

    Article  PubMed  Google Scholar 

  173. Moulin, P. et al. Identification and diagnosis of patients with familial chylomicronaemia syndrome (FCS): Expert panel recommendations and proposal of an “FCS score”. Atherosclerosis 275, 265–272 (2018).

    Article  CAS  PubMed  Google Scholar 

  174. Gill, P. K., Dron, J. S. & Hegele, R. A. Genetics of hypertriglyceridemia and atherosclerosis. Curr. Opin. Cardiol. 36, 264–271 (2021).

    Article  PubMed  Google Scholar 

  175. Pedersen, S. B., Langsted, A. & Nordestgaard, B. G. Nonfasting mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis. JAMA Intern. Med. 176, 1834–1842 (2016).

    Article  PubMed  Google Scholar 

  176. Hansen, S. E. J., Madsen, C. M., Varbo, A., Tybjaerg-Hansen, A. & Nordestgaard, B. G. Genetic variants associated with increased plasma levels of triglycerides, via effects on the lipoprotein lipase pathway, increase risk of acute pancreatitis. Clin. Gastroenterol. Hepatol. 19, 1652–1660.e6 (2021).

    Article  CAS  PubMed  Google Scholar 

  177. Hansen, S. E. J., Madsen, C. M., Varbo, A. & Nordestgaard, B. G. Body mass index, triglycerides, and risk of acute pancreatitis: a population-based study of 118 000 individuals. J. Clin. Endocrinol. Metab. 105, dgz059 (2020).

    Article  PubMed  Google Scholar 

  178. Mach, F. et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur. Heart J. 41, 111–188 (2020).

    Article  PubMed  Google Scholar 

  179. Kotseva, K. et al. Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: results from the european society of cardiology ESC-EORP EUROASPIRE V registry. Eur. J. Prev. Cardiol. 26, 824–835 (2019).

    Article  PubMed  Google Scholar 

  180. Arnett, D. K. et al. 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J. Am. Coll. Cardiol. 74, 1376–1414 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Blaak, E. E., Riccardi, G. & Cho, L. Carbohydrates: separating fact from fiction. Atherosclerosis 328, 114–123 (2021).

    Article  CAS  PubMed  Google Scholar 

  182. Martinez-Gonzalez, M. A. et al. Carbohydrate quality changes and concurrent changes in cardiovascular risk factors: a longitudinal analysis in the PREDIMED-Plus randomized trial. Am. J. Clin. Nutr. 111, 291–306 (2020).

    Article  PubMed  Google Scholar 

  183. Sacks, F. M. et al. Dietary fats and cardiovascular disease: a presidential advisory from the American Heart Association. Circulation 136, e1–e23 (2017).

    Article  PubMed  Google Scholar 

  184. Ruscica, M., Ferri, N., Santos, R. D., Sirtori, C. R. & Corsini, A. Lipid lowering drugs: present status and future developments. Curr. Atheroscler. Rep. 23, 17 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Watts, G. F., Raal, F. J. & Chan, D. C. Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3. Future Cardiol. 18, 143–153 (2021).

    Article  PubMed  CAS  Google Scholar 

  186. Xu, J. & Ashjian, E. Treatment of hypertriglyceridemia: a review of therapies in the pipeline. J. Pharm. Pract. https://doi.org/10.1177/08971900211053489 (2021).

    Article  PubMed  Google Scholar 

  187. Parhofer, K. G. & Laufs, U. The diagnosis and treatment of hypertriglyceridemia. Dtsch. Arztebl Int. 116, 825–832 (2019).

    PubMed  Google Scholar 

  188. Laufs, U., Parhofer, K. G., Ginsberg, H. N. & Hegele, R. A. Clinical review on triglycerides. Eur. Heart J. 41, 99–109c (2020).

    Article  CAS  PubMed  Google Scholar 

  189. Keech, A. et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 366, 1849–1861 (2005).

    Article  CAS  PubMed  Google Scholar 

  190. Scott, R. et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 32, 493–498 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2010).

    Article  Google Scholar 

  192. Bruckert, E., Labreuche, J., Deplanque, D., Touboul, P. J. & Amarenco, P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J. Cardiovasc. Pharmacol. 57, 267–272 (2011).

    Article  CAS  PubMed  Google Scholar 

  193. Lee, M., Saver, J. L., Towfighi, A., Chow, J. & Ovbiagele, B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis 217, 492–498 (2011).

    Article  CAS  PubMed  Google Scholar 

  194. Araki, E. et al. Effects of pemafibrate, a novel selective PPARalpha modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 41, 538–546 (2018).

    Article  CAS  PubMed  Google Scholar 

  195. Pradhan, A. D. et al. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am. Heart J. 206, 80–93 (2018).

    Article  CAS  PubMed  Google Scholar 

  196. Mangili, O. C. et al. Favorable effects of ezetimibe alone or in association with simvastatin on the removal from plasma of chylomicrons in coronary heart disease subjects. Atherosclerosis 233, 319–325 (2014).

    Article  CAS  PubMed  Google Scholar 

  197. Toth, P. P. et al. Comparing remnant lipoprotein cholesterol measurement methods to evaluate efficacy of ezetimibe/statin vs statin therapy. J. Clin. Lipidol. 13, 997–1007.e8 (2019).

    Article  PubMed  Google Scholar 

  198. Sakamoto, K. et al. Effect of ezetimibe on LDL-C lowering and atherogenic lipoprotein profiles in type 2 diabetic patients poorly controlled by statins. PLoS ONE 10, e0138332 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  199. Ahmed, O. et al. Ezetimibe in combination with simvastatin reduces remnant cholesterol without affecting biliary lipid concentrations in gallstone patients. J. Am. Heart Assoc. 7, e009876 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Morrone, D. et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 223, 251–261 (2012).

    Article  CAS  PubMed  Google Scholar 

  201. Tremblay, A. J., Lamarche, B., Cohn, J. S., Hogue, J. C. & Couture, P. Effect of ezetimibe on the in vivo kinetics of apoB-48 and apoB-100 in men with primary hypercholesterolemia. Arterioscler. Thromb. Vasc. Biol. 26, 1101–1106 (2006).

    Article  CAS  PubMed  Google Scholar 

  202. Arsenault, B. J., Perrot, N. & Puri, R. Therapeutic agents targeting cardiometabolic risk for preventing and treating atherosclerotic cardiovascular diseases. Clin. Pharmacol. Ther. 104, 257–268 (2018).

    Article  CAS  PubMed  Google Scholar 

  203. Blom, D. J., Raal, F. J., Santos, R. D. & Marais, A. D. Lomitapide and mipomersen-inhibiting microsomal triglyceride transfer protein (MTP) and apoB100 synthesis. Curr. Atheroscler. Rep. 21, 48 (2019).

    Article  CAS  PubMed  Google Scholar 

  204. Gallo, A., Beliard, S., D’Erasmo, L. & Bruckert, E. Familial chylomicronemia syndrome (FCS): recent data on diagnosis and treatment. Curr. Atheroscler. Rep. 22, 63 (2020).

    Article  CAS  PubMed  Google Scholar 

  205. Casula, M. et al. Omega-3 polyunsaturated fatty acids supplementation and cardiovascular outcomes: do formulation, dosage, and baseline cardiovascular risk matter? An updated meta-analysis of randomized controlled trials. Pharmacol. Res. 160, 105060 (2020).

    Article  CAS  PubMed  Google Scholar 

  206. Marston, N. A. et al. Association between triglyceride lowering and reduction of cardiovascular risk across multiple lipid-lowering therapeutic classes: a systematic review and meta-regression analysis of randomized controlled trials. Circulation 140, 1308–1317 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Nicholls, S. J. et al. Effect of high-dose omega-3 fatty acids vs corn oil on major adverse cardiovascular events in patients at high cardiovascular risk: the strength randomized clinical trial. JAMA 324, 2268–2280 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Nicholls, S. J. et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin. Cardiol. 41, 1281–1288 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Bhatt, D. L. et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380, 11–22 (2019).

    Article  CAS  PubMed  Google Scholar 

  210. Doi, T., Langsted, A. & Nordestgaard, B. G. A possible explanation for the contrasting results of REDUCE-IT vs. STRENGTH: cohort study mimicking trial designs. Eur. Heart J. 42, 4807–4817 (2021).

    Article  CAS  PubMed  Google Scholar 

  211. Gencer, B. et al. Effect of long-term marine omega-3 fatty acids supplementation on the risk of atrial fibrillation in randomized controlled trials of cardiovascular outcomes: a systematic review and meta-analysis. Circulation 144, 1981–1990 (2021).

    Article  CAS  PubMed  Google Scholar 

  212. Macchi, C. et al. A new dawn for managing dyslipidemias: the era of RNA-based therapies. Pharmacol. Res. 150, 104413 (2019).

    Article  CAS  PubMed  Google Scholar 

  213. Tsimikas, S. RNA-targeted therapeutics for lipid disorders. Curr. Opin. Lipidol. 29, 459–466 (2018).

    Article  CAS  PubMed  Google Scholar 

  214. Raal, F. J. et al. Evinacumab for homozygous familial hypercholesterolemia. N. Engl. J. Med. 383, 711–720 (2020).

    Article  CAS  PubMed  Google Scholar 

  215. Hsieh, J. & Adeli, K. Regulation of intestinal chylomicron production by glucagon-like peptides. Cardiovasc. Hematol. Disord. Drug Targets 12, 92–97 (2012).

    Article  CAS  PubMed  Google Scholar 

  216. Packard, C. J., Munro, A., Lorimer, A. R., Gotto, A. M. & Shepherd, J. Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects. J. Clin. Invest. 74, 2178–2192 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Boren, J. et al. The assembly and secretion of apoB 100 containing lipoproteins in Hep G2 cells. Evidence for different sites for protein synthesis and lipoprotein assembly. J. Biol. Chem. 265, 10556–10564 (1990).

    Article  CAS  PubMed  Google Scholar 

  218. Ginsberg, H. N. Role of lipid synthesis, chaperone proteins and proteasomes in the assembly and secretion of apoprotein B-containing lipoproteins from cultured liver cells. Clin. Exp. Pharmacol. Physiol. 24, A29–A32 (1997).

    Article  CAS  PubMed  Google Scholar 

  219. Zhang, X. & Fernandez-Hernando, C. Transport of LDLs into the arterial wall: impact in atherosclerosis. Curr. Opin. Lipidol. 31, 279–285 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Huang, L. et al. SR-B1 drives endothelial cell LDL transcytosis via DOCK4 to promote atherosclerosis. Nature 569, 565–569 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Tabas, I., Williams, K. J. & Boren, J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 116, 1832–1844 (2007).

    Article  CAS  PubMed  Google Scholar 

  222. Camejo, G. The interaction of lipids and lipoproteins with the intercellular matrix of arterial tissue: its possible role in atherogenesis. Adv. Lipid Res. 19, 1–53 (1982).

    Article  CAS  PubMed  Google Scholar 

  223. Proctor, S. D. & Mamo, J. C. Intimal retention of cholesterol derived from apolipoprotein B100- and apolipoprotein B48-containing lipoproteins in carotid arteries of Watanabe heritable hyperlipidemic rabbits. Arterioscler. Thromb. Vasc. Biol. 23, 1595–1600 (2003).

    Article  CAS  PubMed  Google Scholar 

  224. Flood, C. et al. Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100. Arterioscler. Thromb. Vasc. Biol. 24, 564–570 (2004).

    Article  CAS  PubMed  Google Scholar 

  225. Hiukka, A. et al. ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan. Diabetes 58, 2018–2026 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Johannesen, C. D. L., Mortensen, M. B., Langsted, A. & Nordestgaard, B. G. Apolipoprotein B and non-HDL cholesterol better reflect residual risk than LDL cholesterol in statin-treated patients. J. Am. Coll. Cardiol. 77, 1439–1450 (2021).

    Article  CAS  PubMed  Google Scholar 

  227. Balling, M. et al. VLDL cholesterol accounts for one-half of the risk of myocardial infarction associated with apob-containing lipoproteins. J. Am. Coll. Cardiol. 76, 2725–2735 (2020).

    Article  CAS  PubMed  Google Scholar 

  228. Nordestgaard, B. G. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ. Res. 118, 547–563 (2016).

    Article  CAS  PubMed  Google Scholar 

  229. Nakajima, K. et al. Postprandial lipoprotein metabolism: VLDL vs chylomicrons. Clin. Chim. Acta 412, 1306–1318 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors acknowledge funding from the Swedish Research Council, the Swedish Heart–Lung Foundation, the Swedish state under the agreement between the Swedish government and the county councils (ALFGBG-965404; J.B.), and the Finnish Foundation of Cardiovascular Research (M.-R.T.). The authors thank R. Perkins (University of Gothenburg, Sweden) for help with editing this manuscript.

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Authors and Affiliations

  1. Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden

    Jan Borén & Elias Björnson

  2. Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    Marja-Riitta Taskinen

  3. Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK

    Chris J. Packard

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  1. Jan Borén
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  2. Marja-Riitta Taskinen
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  3. Elias Björnson
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J.B., M.-R.T. and C.J.P. researched data for this manuscript. All the authors contributed to the discussion of its content and wrote, reviewed and edited the manuscript before submission.

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Correspondence to Jan Borén.

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Nature Reviews Cardiology thanks David Cohen, who co-reviewed with Michele Alves-Bezerra; Daniel Rader; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Borén, J., Taskinen, MR., Björnson, E. et al. Metabolism of triglyceride-rich lipoproteins in health and dyslipidaemia. Nat Rev Cardiol 19, 577–592 (2022). https://doi.org/10.1038/s41569-022-00676-y

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