Skip to main content
SpringerLink
Log in

Production and Metabolism of Triglyceride-Rich Lipoproteins in Both the Normal and Diabetic States

  • Chapter
  • First Online:
Lipoproteins in Diabetes Mellitus

Part of the book series: Contemporary Diabetes ((CDI))

Abstract

Low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and chylomicrons are referred to as apolipoprotein B (apoB)-containing lipoproteins and exhibit pro-atherogenic characteristics. VLDL, which transport endogenous lipids, are produced by the liver, while chylomicrons, which transport diet-derived lipids, are produced by the intestine. After lipoprotein secretion, triglycerides are hydrolyzed by lipoprotein lipase, and fatty acids are taken up by the cells to provide energy (in the muscle) or to be stored (in adipose tissue). The resulting remnant lipoproteins become enriched in cholesterol and can be taken up by cells.

Insulin plays a regulatory key role in the metabolism of these triglyceride (TG)-rich lipoproteins. Insulin resistance is a condition of reduced responsiveness of tissues (liver, muscle, and adipose tissue) to normal circulating levels of insulin, and is a feature of several diseases, including type 2 diabetes, obesity, dyslipidemia, and hypertension. As a result, insulin production increases to maintain normal levels of blood glucose. Insulin resistance can generate lipoprotein abnormalities, such as increased plasma levels of VLDL triglyceride and apoB100, reduced plasma levels of HDL and apoA-I, and relatively normal LDL levels with increase of small dense LDL particles.

TG-rich lipoproteins induce vascular dysfunction: endothelial function becomes impaired in the presence of hypertriglyceridemia, with increased expression of adhesion molecules and chemotactic factors involved in the inflammatory process; moreover, lipid deposition within arterial macrophages is enhanced, thus contributing to the generation of foam cells. These findings are in line with the idea that TG-rich lipoproteins may play a key role in the early stages of atherogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. 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. 1995;15: 199–207.

    CAS  PubMed  Google Scholar 

  2. Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia. 2003;46: 733–49.

    PubMed  Google Scholar 

  3. Chen SH, Habib G, Yang CY, et al. Apolipoprotein B-48 is the product of a messenger RNA with an organ-specific in-frame stop codon. Science. 1987;238:363–6.

    CAS  PubMed  Google Scholar 

  4. Powell LM, Wallis SC, Pease RJ, Edwards YH, Knott TJ, Scott J. A novel form of tissue-specific RNA processing produces apolipoprotein-B48 in intestine. Cell. 1987;50:831–40.

    CAS  PubMed  Google Scholar 

  5. Pan X, Hussain MM. Diurnal regulation of microsomal triglyceride transfer protein and plasma lipid levels. J Biol Chem. 2007;282:24707–19.

    CAS  PubMed  Google Scholar 

  6. Fisher EA, Pan M, Chen X, et al. The triple threat to nascent apolipoprotein B. Evidence for multiple, distinct degradative pathways. J Biol Chem. 2001;276:27855–63.

    CAS  PubMed  Google Scholar 

  7. Benoist F, Grand-Perret T. Co-translational degradation of apolipoprotein B100 by the proteasome is prevented by microsomal triglyceride transfer protein. Synchronized translation studies on HepG2 cells treated with an inhibitor of microsomal triglyceride transfer protein. J Biol Chem. 1997;272:20435–42.

    CAS  PubMed  Google Scholar 

  8. Dixon JL, Furukawa S, Ginsberg HN. Oleate stimulates secretion of apolipoprotein B-containing lipoproteins from Hep G2 cells by inhibiting early intracellular degradation of apolipoprotein B. J Biol Chem. 1991;266:5080–6.

    CAS  PubMed  Google Scholar 

  9. Zhou M, Fisher EA, Ginsberg HN. Regulated Co-translational ubiquitination of apolipoprotein B100. A new paradigm for proteasomal degradation of a secretory protein. J Biol Chem. 1998;273: 24649–53.

    CAS  PubMed  Google Scholar 

  10. Williams KJ, Brocia RW, Fisher EA. The unstirred water layer as a site of control of apolipoprotein B secretion. J Biol Chem. 1990;265:16741–4.

    CAS  PubMed  Google Scholar 

  11. Schumaker VN, Phillips ML, Chatterton JE. Apolipoprotein B and low-density lipoprotein structure: implications for biosynthesis of triglyceride-rich lipoproteins. Adv Protein Chem. 1994;45:205–48.

    CAS  PubMed  Google Scholar 

  12. Gordon DA, Wetterau JR, Gregg RE. Microsomal triglyceride transfer protein: a protein complex required for the assembly of lipoprotein particles. Trends Cell Biol. 1995;5:317–21.

    CAS  PubMed  Google Scholar 

  13. Rustaeus S, Stillemark P, Lindberg K, Gordon D, Olofsson SO. 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. 1998;273: 5196–203.

    CAS  PubMed  Google Scholar 

  14. Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res. 2003;44:22–32.

    CAS  PubMed  Google Scholar 

  15. Jamil H, Chu CH, Dickson Jr JK, et al. Evidence that microsomal triglyceride transfer protein is limiting in the production of apolipoprotein B-containing lipoproteins in hepatic cells. J Lipid Res. 1998;39: 1448–54.

    CAS  PubMed  Google Scholar 

  16. Hui TY, Olivier LM, Kang S, Davis RA. Microsomal triglyceride transfer protein is essential for hepatic secretion of apoB-100 and apoB-48 but not triglyceride. J Lipid Res. 2002;43:785–93.

    CAS  PubMed  Google Scholar 

  17. Manchekar M, Richardson PE, Forte TM, Datta G, Segrest JP, Dashti N. Apolipoprotein B-containing lipoprotein particle assembly: lipid capacity of the nascent lipoprotein particle. J Biol Chem. 2004;279: 39757–66.

    CAS  PubMed  Google Scholar 

  18. Alexander CA, Hamilton RL, Havel RJ. Subcellular localization of B apoprotein of plasma lipoproteins in rat liver. J Cell Biol. 1976;69:241–63.

    CAS  PubMed  Google Scholar 

  19. Wu X, Shang A, Jiang H, Ginsberg HN. Low rates of apoB secretion from HepG2 cells result from reduced delivery of newly synthesized triglyceride to a “secretion-coupled” pool. J Lipid Res. 1996;37:1198–206.

    CAS  PubMed  Google Scholar 

  20. Gibbons GF, Islam K, Pease RJ. Mobilisation of triacylglycerol stores. Biochim Biophys Acta. 2000;1483:37–57.

    CAS  PubMed  Google Scholar 

  21. Gibbons GF, Bartlett SM, Sparks CE, Sparks JD. Extracellular fatty acids are not utilized directly for the synthesis of very-low-density lipoprotein in primary cultures of rat hepatocytes. Biochem J. 1992;287(Pt 3):749–53.

    CAS  PubMed  Google Scholar 

  22. Fisher EA, Ginsberg HN. Complexity in the secretory pathway: the assembly and secretion of apolipoprotein B-containing lipoproteins. J Biol Chem. 2002;277:17377–80.

    CAS  PubMed  Google Scholar 

  23. Pan M, Liang Js JS, Fisher EA, Ginsberg HN. The late addition of core lipids to nascent apolipoprotein B100, resulting in the assembly and secretion of triglyceride-rich lipoproteins, is independent of both microsomal triglyceride transfer protein activity and new triglyceride synthesis. J Biol Chem. 2002;277:4413–21.

    CAS  PubMed  Google Scholar 

  24. Wiggins D, Gibbons GF. The lipolysis/esterification cycle of hepatic triacylglycerol. Its role in the secretion of very-low-density lipoprotein and its response to hormones and sulphonylureas. Biochem J. 1992;284(Pt 2):457–62.

    CAS  PubMed  Google Scholar 

  25. Malmstrom R, Packard CJ, Watson TD, et al. Metabolic basis of hypotriglyceridemic effects of insulin in normal men. Arterioscler Thromb Vasc Biol. 1997;17:1454–64.

    CAS  PubMed  Google Scholar 

  26. Packard CJ, Munro A, Lorimer AR, Gotto AM, Shepherd J. Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects. J Clin Invest. 1984;74:2178–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gaw A, Packard CJ, Lindsay GM, 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. 1995;36:158–71.

    CAS  PubMed  Google Scholar 

  28. Black DD. Development and physiological regulation of intestinal lipid absorption. I. Development of intestinal lipid absorption: cellular events in chylomicron assembly and secretion. Am J Physiol Gastrointest Liver Physiol. 2007;293:G519–24.

    CAS  PubMed  Google Scholar 

  29. Williams KJ, Chen K. Recent insights into factors affecting remnant lipoprotein uptake. Curr Opin Lipidol. 2010;21:218–28.

    CAS  PubMed  Google Scholar 

  30. Fuki IV, Kuhn KM, Lomazov IR, et al. The syndecan family of proteoglycans. Novel receptors mediating internalization of atherogenic lipoproteins in vitro. J Clin Invest. 1997;100:1611–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Mahley RW, Huang Y. Atherogenic remnant lipoproteins: role for proteoglycans in trapping, transferring, and internalizing. J Clin Invest. 2007;117: 94–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Mahley RW, Ji ZS. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res. 1999;40:1–16.

    CAS  PubMed  Google Scholar 

  33. Mahley RW, Weisgraber KH, Innerarity TL, Rall Jr SC. Genetic defects in lipoprotein metabolism. Elevation of atherogenic lipoproteins caused by impaired catabolism. JAMA. 1991;265:78–83.

    CAS  PubMed  Google Scholar 

  34. Williams KJ, Fuki IV. Cell-surface heparan sulfate proteoglycans: dynamic molecules mediating ligand catabolism. Curr Opin Lipidol. 1997;8:253–62.

    CAS  PubMed  Google Scholar 

  35. Cooper AD. Hepatic uptake of chylomicron remnants. J Lipid Res. 1997;38:2173–92.

    CAS  PubMed  Google Scholar 

  36. Lewis GF, Uffelman KD, Szeto LW, 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. 1995;95: 158–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. den Boer MA, Voshol PJ, Kuipers F, Romijn JA, Havekes LM. Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production. Am J Physiol Endocrinol Metab. 2006;291:E1360–4.

    Google Scholar 

  38. Lewis GF, Steiner G. Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state. Diabetes Care. 1996;19:390–3.

    CAS  PubMed  Google Scholar 

  39. Sparks JD, Sparks CE. Insulin regulation of triacylglycerol-rich lipoprotein synthesis and secretion. Biochim Biophys Acta. 1994;1215:9–32.

    CAS  PubMed  Google Scholar 

  40. Malmstrom R, Packard CJ, Caslake M, et al. Effects of insulin and acipimox on VLDL1 and VLDL2 apolipoprotein B production in normal subjects. Diabetes. 1998;47:779–87.

    CAS  PubMed  Google Scholar 

  41. Dashti N, Williams DL, Alaupovic P. Effects of oleate and insulin on the production rates and cellular mRNA concentrations of apolipoproteins in HepG2 cells. J Lipid Res. 1989;30:1365–73.

    CAS  PubMed  Google Scholar 

  42. Sparks CE, Sparks JD, Bolognino M, Salhanick A, Strumph PS, Amatruda JM. Insulin effects on apolipoprotein B lipoprotein synthesis and secretion by primary cultures of rat hepatocytes. Metabolism. 1986;35:1128–36.

    CAS  PubMed  Google Scholar 

  43. Sparks JD, Sparks CE. Insulin modulation of hepatic synthesis and secretion of apolipoprotein B by rat hepatocytes. J Biol Chem. 1990;265:8854–62.

    CAS  PubMed  Google Scholar 

  44. Sparks JD, Sparks CE, Miller LL. Insulin effects on apolipoprotein B production by normal, diabetic and treated-diabetic rat liver and cultured rat hepatocytes. Biochem J. 1989;261:83–8.

    CAS  PubMed  Google Scholar 

  45. Stein DT, Esser V, Stevenson BE, et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J Clin Invest. 1996;97:2728–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Sparks JD, Collins HL, Chirieac DV, et al. Hepatic very-low-density lipoprotein and apolipoprotein B production are increased following in vivo induction of betaine-homocysteine S-methyltransferase. Biochem J. 2006;395:363–71.

    CAS  PubMed  Google Scholar 

  47. Sparks JD, Sparks CE, Bolognino M, Roncone AM, Jackson TK, Amatruda JM. Effects of nonketotic streptozotocin diabetes on apolipoprotein B synthesis and secretion by primary cultures of rat hepatocytes. J Clin Invest. 1988;82:37–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kamagate A, Qu S, Perdomo G, et al. FoxO1 mediates insulin-dependent regulation of hepatic VLDL production in mice. J Clin Invest. 2008;118:2347–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Qu S, Su D, Altomonte J, et al. PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1. Am J Physiol Endocrinol Metab. 2007;292:E421–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab. 2007;6:208–16.

    CAS  PubMed  Google Scholar 

  51. Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007;129:1261–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis. 2011;217:3–46.

    CAS  PubMed  Google Scholar 

  53. Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med. 2006;119:S10–6.

    PubMed  PubMed Central  Google Scholar 

  54. Reaven GM. Why Syndrome X? From Harold Himsworth to the insulin resistance syndrome. Cell Metab. 2005;1:9–14.

    CAS  PubMed  Google Scholar 

  55. American Diabetes Association (2007) Diagnosis and classification of diabetes mellitus. Diabetes Care 30(Suppl 1):S42–47

    Google Scholar 

  56. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415–28.

    CAS  PubMed  Google Scholar 

  57. Sesti G. Pathophysiology of insulin resistance. Best Pract Res Clin Endocrinol Metab. 2006;20:665–79.

    CAS  PubMed  Google Scholar 

  58. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006;7:85–96.

    CAS  PubMed  Google Scholar 

  59. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53:1270–87.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Morino K, Petersen KF, Shulman GI. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes. 2006;55 Suppl 2:S9–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674–82.

    CAS  PubMed  Google Scholar 

  62. Bartels ED, Lauritsen M, Nielsen LB. Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. Diabetes. 2002;51:1233–9.

    CAS  PubMed  Google Scholar 

  63. Kuriyama H, Yamashita S, Shimomura I, et al. Enhanced expression of hepatic acyl-coenzyme A synthetase and microsomal triglyceride transfer protein messenger RNAs in the obese and hypertriglyceridemic rat with visceral fat accumulation. Hepatology. 1998;27:557–62.

    CAS  PubMed  Google Scholar 

  64. Taghibiglou C, Carpentier A, Van Iderstine SC, et al. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem. 2000;275:8416–25.

    CAS  PubMed  Google Scholar 

  65. Carpentier A, Taghibiglou C, Leung N, et al. Ameliorated hepatic insulin resistance is associated with normalization of microsomal triglyceride transfer protein expression and reduction in very low density lipoprotein assembly and secretion in the fructose-fed hamster. J Biol Chem. 2002;277:28795–802.

    CAS  PubMed  Google Scholar 

  66. Chong T, Naples M, Federico L, et al. Effect of rosuvastatin on hepatic production of apolipoprotein B-containing lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia. Atherosclerosis. 2006;185:21–31.

    CAS  PubMed  Google Scholar 

  67. Chahil TJ, Ginsberg HN. Diabetic dyslipidemia. Endocrinol Metab Clin North Am. 2006;35:491–510. vii–viii.

    CAS  PubMed  Google Scholar 

  68. Malmstrom R, Packard CJ, Caslake M, et al. Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM. Diabetologia. 1997;40:454–62.

    CAS  PubMed  Google Scholar 

  69. Lewis GF, Uffelman KD, Szeto LW, Steiner G. Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals. Diabetes. 1993;42:833–42.

    CAS  PubMed  Google Scholar 

  70. Au WS, Kung HF, Lin MC. Regulation of microsomal triglyceride transfer protein gene by insulin in HepG2 cells: roles of MAPKerk and MAPKp38. Diabetes. 2003;52:1073–80.

    CAS  PubMed  Google Scholar 

  71. Brown AM, Gibbons GF. Insulin inhibits the maturation phase of VLDL assembly via a phosphoinositide 3-kinase-mediated event. Arterioscler Thromb Vasc Biol. 2001;21:1656–61.

    CAS  PubMed  Google Scholar 

  72. Bartlett SM, Gibbons GF. Short- and longer-term regulation of very-low-density lipoprotein secretion by insulin, dexamethasone and lipogenic substrates in cultured hepatocytes. A biphasic effect of insulin. Biochem J. 1988;249:37–43.

    CAS  PubMed  Google Scholar 

  73. Cummings MH, Watts GF, Pal C, et al. Increased hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 in obesity: a stable isotope study. Clin Sci (Lond). 1995;88:225–33.

    CAS  Google Scholar 

  74. Gill JM, Brown JC, Bedford D, et al. Hepatic production of VLDL1 but not VLDL2 is related to insulin resistance in normoglycaemic middle-aged subjects. Atherosclerosis. 2004;176:49–56.

    CAS  PubMed  Google Scholar 

  75. Riches FM, Watts GF, Naoumova RP, Kelly JM, Croft KD, Thompson GR. Hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity. Int J Obes Relat Metab Disord. 1998;22:414–23.

    CAS  PubMed  Google Scholar 

  76. Sniderman AD, Cianflone K. Substrate delivery as a determinant of hepatic apoB secretion. Arterioscler Thromb. 1993;13:629–36.

    CAS  PubMed  Google Scholar 

  77. Basu A, Basu R, Shah P, Vella A, Rizza RA, Jensen MD. Systemic and regional free fatty acid metabolism in type 2 diabetes. Am J Physiol Endocrinol Metab. 2001;280:E1000–6.

    CAS  PubMed  Google Scholar 

  78. Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology. 2008;134:424–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Jafri H, Alsheikh-Ali AA, Karas RH. Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy. J Am Coll Cardiol. 2010;55:2846–54.

    CAS  PubMed  Google Scholar 

  80. Ginsberg HN, Zhang YL, Hernandez-Ono A. Regulation of plasma triglycerides in insulin resistance and diabetes. Arch Med Res. 2005;36:232–40.

    CAS  PubMed  Google Scholar 

  81. Duez H, Lamarche B, Uffelman KD, Valero R, Cohn JS, Lewis GF. Hyperinsulinemia is associated with increased production rate of intestinal apolipoprotein B-48-containing lipoproteins in humans. Arterioscler Thromb Vasc Biol. 2006;26:1357–63.

    CAS  PubMed  Google Scholar 

  82. Cohn JS, Patterson BW, Uffelman KD, Davignon J, Steiner G. Rate of production of plasma and very-low-density lipoprotein (VLDL) apolipoprotein C-III is strongly related to the concentration and level of production of VLDL triglyceride in male subjects with different body weights and levels of insulin sensitivity. J Clin Endocrinol Metab. 2004;89:3949–55.

    CAS  PubMed  Google Scholar 

  83. Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109:1125–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev. 2000;14:2831–8.

    CAS  PubMed  Google Scholar 

  85. Cha JY, Repa JJ. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate-response element-binding protein is a target gene of LXR. J Biol Chem. 2007;282:743–51.

    CAS  PubMed  Google Scholar 

  86. Chen G, Liang G, Ou J, Goldstein JL, Brown MS. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci USA. 2004;101:11245–50.

    CAS  PubMed  Google Scholar 

  87. Hegarty BD, Bobard A, Hainault I, Ferre P, Bossard P, Foufelle F. Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c. Proc Natl Acad Sci USA. 2005;102:791–6.

    CAS  PubMed  Google Scholar 

  88. Brunzell JD, Hazzard WR, Porte Jr D, Bierman EL. Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man. J Clin Invest. 1973;52:1578–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Duez H, Lamarche B, Valero R, et al. Both intestinal and hepatic lipoprotein production are stimulated by an acute elevation of plasma free fatty acids in humans. Circulation. 2008;117:2369–76.

    CAS  PubMed  Google Scholar 

  90. Adeli K, Lewis GF. Intestinal lipoprotein overproduction in insulin-resistant states. Curr Opin Lipidol. 2008;19:221–8.

    CAS  PubMed  Google Scholar 

  91. Dane-Stewart CA, Watts GF, Barrett PH, et al. Chylomicron remnant metabolism studied with a new breath test in postmenopausal women with and without type 2 diabetes mellitus. Clin Endocrinol (Oxf). 2003;58:415–20.

    CAS  Google Scholar 

  92. Georgopoulos A, Phair RD. Abnormal clearance of postprandial Sf 100-400 plasma lipoproteins in insulin-dependent diabetes mellitus. J Lipid Res. 1991;32:1133–41.

    CAS  PubMed  Google Scholar 

  93. Han S, Liang CP, Westerterp M, et al. Hepatic insulin signaling regulates VLDL secretion and atherogenesis in mice. J Clin Invest. 2009;119:1029–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Niesen M, Bedi M, Lopez D. Diabetes alters LDL receptor and PCSK9 expression in rat liver. Arch Biochem Biophys. 2008;470:111–5.

    CAS  PubMed  Google Scholar 

  95. Grobe K, Esko JD. Regulated translation of heparan sulfate N-acetylglucosamine N-deacetylase/n-sulfotransferase isozymes by structured 5′-untranslated regions and internal ribosome entry sites. J Biol Chem. 2002;277:30699–706.

    CAS  PubMed  Google Scholar 

  96. Williams KJ, Liu ML, Zhu Y, et al. Loss of heparan N-sulfotransferase in diabetic liver: role of angiotensin II. Diabetes. 2005;54:1116–22.

    CAS  PubMed  Google Scholar 

  97. Kjellen L, Bielefeld D, Hook M. Reduced sulfation of liver heparan sulfate in experimentally diabetic rats. Diabetes. 1983;32:337–42.

    CAS  PubMed  Google Scholar 

  98. Ebara T, Conde K, Kako Y, et al. Delayed catabolism of apoB-48 lipoproteins due to decreased heparan sulfate proteoglycan production in diabetic mice. J Clin Invest. 2000;105:1807–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Anisfeld AM, Kast-Woelbern HR, Meyer ME, et al. Syndecan-1 expression is regulated in an isoform-specific manner by the farnesoid-X receptor. J Biol Chem. 2003;278:20420–8.

    CAS  PubMed  Google Scholar 

  100. Duran-Sandoval D, Mautino G, Martin G, et al. Glucose regulates the expression of the farnesoid X receptor in liver. Diabetes. 2004;53:890–8.

    CAS  PubMed  Google Scholar 

  101. Olsson U, Egnell AC, Lee MR, et al. Changes in matrix proteoglycans induced by insulin and fatty acids in hepatic cells may contribute to dyslipidemia of insulin resistance. Diabetes. 2001;50:2126–32.

    CAS  PubMed  Google Scholar 

  102. Rohrbach DH, Hassell JR, Kleinman HK, Martin GR. Alterations in the basement membrane (heparan sulfate) proteoglycan in diabetic mice. Diabetes. 1982;31:185–8.

    CAS  PubMed  Google Scholar 

  103. Chen K, Liu ML, Schaffer L, et al. Type 2 diabetes in mice induces hepatic overexpression of sulfatase 2, a novel factor that suppresses uptake of remnant lipoproteins. Hepatology. 2010;52:1957–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Steinberg HO, Tarshoby M, Monestel R, et al. Elevated circulating free fatty acid levels impair endothelium-dependent vasodilation. J Clin Invest. 1997;100:1230–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Anderson RA, Evans ML, Ellis GR, et al. The relationships between post-prandial lipaemia, endothelial function and oxidative stress in healthy individuals and patients with type 2 diabetes. Atherosclerosis. 2001;154:475–83.

    CAS  PubMed  Google Scholar 

  106. Maggi FM, Raselli S, Grigore L, Redaelli L, Fantappie S, Catapano AL. Lipoprotein remnants and endothelial dysfunction in the postprandial phase. J Clin Endocrinol Metab. 2004;89:2946–50.

    CAS  PubMed  Google Scholar 

  107. Ferreira AC, Peter AA, Mendez AJ, et al. Postprandial hypertriglyceridemia increases circulating levels of endothelial cell microparticles. Circulation. 2004;110:3599–603.

    PubMed  Google Scholar 

  108. Burdge GC, Calder PC. Plasma cytokine response during the postprandial period: a potential causal process in vascular disease? Br J Nutr. 2005;93:3–9.

    CAS  PubMed  Google Scholar 

  109. Lundman P, Eriksson MJ, Silveira A, et al. Relation of hypertriglyceridemia to plasma concentrations of biochemical markers of inflammation and endothelial activation (C-reactive protein, interleukin-6, soluble adhesion molecules, von Willebrand factor, and endothelin-1). Am J Cardiol. 2003;91:1128–31.

    CAS  PubMed  Google Scholar 

  110. Nappo F, Esposito K, Cioffi M, et al. Postprandial endothelial activation in healthy subjects and in type 2 diabetic patients: role of fat and carbohydrate meals. J Am Coll Cardiol. 2002;39:1145–50.

    CAS  PubMed  Google Scholar 

  111. Eiselein L, Wilson DW, Lame MW, Rutledge JC. Lipolysis products from triglyceride-rich lipoproteins increase endothelial permeability, perturb zonula occludens-1 and F-actin, and induce apoptosis. Am J Physiol Heart Circ Physiol. 2007;292:H2745–53.

    CAS  PubMed  Google Scholar 

  112. Banfi C, Mussoni L, Rise P, et al. Very low density lipoprotein-mediated signal transduction and plasminogen activator inhibitor type 1 in cultured HepG2 cells. Circ Res. 1999;85:208–17.

    CAS  PubMed  Google Scholar 

  113. Dichtl W, Nilsson L, Goncalves I, et al. Very low-density lipoprotein activates nuclear factor-kappaB in endothelial cells. Circ Res. 1999;84:1085–94.

    CAS  PubMed  Google Scholar 

  114. Stiko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis. 1990;10:1067–73.

    CAS  PubMed  Google Scholar 

  115. Norata GD, Grigore L, Raselli S, et al. Triglyceride-rich lipoproteins from hypertriglyceridemic subjects induce a pro-inflammatory response in the endothelium: Molecular mechanisms and gene expression studies. J Mol Cell Cardiol. 2006;40:484–94.

    CAS  PubMed  Google Scholar 

  116. Williams CM, Maitin V, Jackson KG. Triacylglycerol-rich lipoprotein-gene interactions in endothelial cells. Biochem Soc Trans. 2004;32:994–8.

    CAS  PubMed  Google Scholar 

  117. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B–12.

    CAS  PubMed  Google Scholar 

  118. Sniderman AD. Postprandial hypertriglyceridemia(s): time to enlarge our pathophysiologic perspective. Eur J Clin Invest. 2000;30:935–7.

    CAS  PubMed  Google Scholar 

  119. Norata GD, Grigore L, Raselli S, et al. Post-prandial endothelial dysfunction in hypertriglyceridemic subjects: molecular mechanisms and gene expression studies. Atherosclerosis. 2007;193:321–7.

    CAS  PubMed  Google Scholar 

  120. Constans J, Conri C. Circulating markers of endothelial function in cardiovascular disease. Clin Chim Acta. 2006;368:33–47.

    CAS  PubMed  Google Scholar 

  121. Mamo JC, Wheeler JR. Chylomicrons or their remnants penetrate rabbit thoracic aorta as efficiently as do smaller macromolecules, including low-density lipoprotein, high-density lipoprotein, and albumin. Coron Artery Dis. 1994;5:695–705.

    CAS  PubMed  Google Scholar 

  122. Proctor SD, Mamo JC. Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall–evidence that plaque cholesterol may be derived from post-prandial lipoproteins. Eur J Clin Invest. 1998;28:497–503.

    CAS  PubMed  Google Scholar 

  123. Rapp JH, Lespine A, Hamilton RL, et al. Triglyceride-rich lipoproteins isolated by selected-affinity anti-apolipoprotein B immunosorption from human atherosclerotic plaque. Arterioscler Thromb. 1994;14:1767–74.

    CAS  PubMed  Google Scholar 

  124. Sattar N, Petrie JR, Jaap AJ. The atherogenic lipoprotein phenotype and vascular endothelial dysfunction. Atherosclerosis. 1998;138:229–35.

    CAS  PubMed  Google Scholar 

  125. Carantoni M, Abbasi F, Chu L, et al. Adherence of mononuclear cells to endothelium in vitro is increased in patients with NIDDM. Diabetes Care. 1997;20:1462–5.

    CAS  PubMed  Google Scholar 

  126. Bates SR, Murphy PL, Feng ZC, Kanazawa T, Getz GS. Very low density lipoproteins promote triglyceride accumulation in macrophages. Arteriosclerosis. 1984;4:103–14.

    CAS  PubMed  Google Scholar 

  127. Saito M, Eto M, Okada M, Iwashima Y, Makino I. Remnant-like particles (RLP) from NIDDM patients with apolipoprotein E3/3 phenotype stimulate cholesteryl ester synthesis in human monocyte-derived macrophages. Artery. 1996;22:155–63.

    CAS  PubMed  Google Scholar 

  128. Fujioka Y, Cooper AD, Fong LG. Multiple processes are involved in the uptake of chylomicron remnants by mouse peritoneal macrophages. J Lipid Res. 1998;39:2339–49.

    CAS  PubMed  Google Scholar 

  129. Cavallero E, Brites F, Delfly B, et al. Abnormal reverse cholesterol transport in controlled type II diabetic patients. Studies on fasting and postprandial LpA-I particles. Arterioscler Thromb Vasc Biol. 1995;15:2130–5.

    CAS  PubMed  Google Scholar 

  130. Syvanne M, Castro G, Dengremont C, et al. Cholesterol efflux from Fu5AH hepatoma cells induced by plasma of subjects with or without coronary artery disease and non-insulin-dependent diabetes: importance of LpA-I:A-II particles and phospholipid transfer protein. Atherosclerosis. 1996;127:245–53.

    CAS  PubMed  Google Scholar 

  131. Palmer AM, Murphy N, Graham A. Triglyceride-rich lipoproteins inhibit cholesterol efflux to apolipoprotein (apo) A1 from human macrophage foam cells. Atherosclerosis. 2004;173:27–38.

    CAS  PubMed  Google Scholar 

  132. Kawakami A, Tanaka A, Nakano T, Saniabadi A, Numano F. Stimulation of arterial smooth muscle cell proliferation by remnant lipoprotein particles isolated by immuno-affinity chromatography with anti-apo A-I and anti-apo B-100. Horm Metab Res. 2001;33:67–72.

    CAS  PubMed  Google Scholar 

  133. Kawakami A, Tanaka A, Chiba T, Nakajima K, Shimokado K, Yoshida M. Remnant lipoprotein-induced smooth muscle cell proliferation involves epidermal growth factor receptor transactivation. Circulation. 2003;108:2679–88.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, and IRCCS Multimedica, Milan, Italy

    Angela Pirillo & Alberico L. Catapano

  2. Department of Pharmacological and Biomolecular Sciences, University of Milan and Center for the Study of Atherosclerosis, E. Bassini Hospital, Cinisello Balsamo, Italy

    Giuseppe D. Norata

  3. Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

    Alberico L. Catapano

Authors
  1. Angela Pirillo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giuseppe D. Norata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alberico L. Catapano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alberico L. Catapano .

Editor information

Editors and Affiliations

  1. NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia

    Alicia J. Jenkins

  2. College of Medicine, University of Illinois, Peoria, Illinois, USA

    Peter P. Toth

  3. Section of Endocrinology and Diabetes Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

    Timothy J. Lyons

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Pirillo, A., Norata, G.D., Catapano, A.L. (2014). Production and Metabolism of Triglyceride-Rich Lipoproteins in Both the Normal and Diabetic States. In: Jenkins, A., Toth, P., Lyons, T. (eds) Lipoproteins in Diabetes Mellitus. Contemporary Diabetes. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-7554-5_6

Download citation

  • DOI: https://doi.org/10.1007/978-1-4614-7554-5_6

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4614-7553-8

  • Online ISBN: 978-1-4614-7554-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation