HDL metabolism in context: Looking on the bright side

Current Opinion in Lipidology

Volumn 19, Issue 4, 2008, Pages 395-404

  Watts, Gerald F ^a   Barrett, P Hugh R ^a   Chan, Dick C ^a  

^a UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

Author keywords

Dyslipoproteinemia; Lipoprotein kinetics; Metabolic syndrome

Indexed keywords

ADIPONECTIN; AMYLOID; ANACETRAPIB; APOLIPOPROTEIN A1; APOLIPOPROTEIN A2; APOLIPOPROTEIN B100; APOLIPOPROTEIN C3; ATORVASTATIN; CHOLESTEROL ESTER TRANSFER PROTEIN; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; ENDOCANNABINOID; FENOFIBRATE; FIBRIC ACID DERIVATIVE; FISH OIL; HIGH DENSITY LIPOPROTEIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; HOMOCYSTEINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LAROPIPRANT; LOW DENSITY LIPOPROTEIN CHOLESTEROL; NICOTINIC ACID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA AGONIST; PIOGLITAZONE; RIMONABANT; ROSIGLITAZONE; ROSUVASTATIN; TORCETRAPIB; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN;

AMINO ACID BLOOD LEVEL; ANTICOAGULATION; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; ATHEROSCLEROSIS; ATHEROSCLEROTIC PLAQUE; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHOLESTEROL TRANSPORT; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; CORONARY ARTERY ATHEROSCLEROSIS; DIABETES MELLITUS; DIABETIC RETINOPATHY; DISEASE EXACERBATION; DOSE RESPONSE; DRUG EFFECT; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; FATTY LIVER; FEEDBACK SYSTEM; HEART INFARCTION; HUMAN; HYPERLIPIDEMIA; HYPERTRIGLYCERIDEMIA; INFLAMMATION; INSULIN RESISTANCE; ISCHEMIC HEART DISEASE; LIFESTYLE; LIPID METABOLISM; LIPID TRANSPORT; LIPOLYSIS; LIVER FUNCTION; METABOLIC REGULATION; METABOLIC SYNDROME X; MONOTHERAPY; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN FUNCTION; PROTEIN SECRETION; PROTEIN SYNTHESIS; PROTEIN SYNTHESIS INHIBITION; REVIEW; RISK REDUCTION; TREATMENT DURATION; TREATMENT OUTCOME; TRIACYLGLYCEROL BLOOD LEVEL; WEIGHT REDUCTION; BLOOD; KINETICS; METABOLISM;

ADIPONECTIN; CHOLESTEROL, HDL; HOMOCYSTEINE; HUMANS; INFLAMMATION; KINETICS;

EID: 53149127349     PISSN: 09579672     EISSN: None     Source Type: Journal    
DOI: 10.1097/MOL.0b013e328306596d     Document Type: Review

References (72)

1. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target: a systematic review. JAMA 2007; 298:786-798.
2. Castelli WP, Garrison RJ, Wilson PW, et al. Incidence of coronary heart disease and lipoprotein cholesterol levels. The Framingham Study. JAMA 1986; 256:2835-2838.
3. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357:2109-2122. This study [Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE)] was the first to examine the clinical outcomes of raising HDL by treatment with the CETP inhibitor torcetrapib in combination with atorvastatin. The trial was terminated prematurely because of an increased mortality and events with intervention.
4. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007; 356: 1304-1316. This study found that in patients with coronary disease torcetrapib treatment had no effect on the progression of coronary atherosclerosis as measured by the percentage atheroma volume change; there was, however, treatment-related improvement in normalized atheroma volume, a secondary endpoint.
5. Bots ML, Visseren FL, Evans GW, et al. Torcetrapib and carotid intima-media thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 2007; 370:153-160.
6. Kastelein JJP, van Leuven SI, Burgess L, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007; 356:1620-1630. These trials [Rating Atherosclerotic Disease Change by Imaging with A New CETP Inhibitor (RADIANCE) I and II] examined the effect of torceptrapib on carotid atherosclerosis in patients with heterozygous familial hypercholesterolemia and mixed dyslipidemia. The use of torcetrapib did not result in reduction of progression of atherosclerosis as assessed by CIMT.
7. Kontush A, Chapman MJ. Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacol Rev 2006; 58:342-374. An excellent review of the concept of HDL functionality.
8. Movva R, Rader DJ. Laboratory assessment of HDL heterogeneity and function. Clin Chem 2008; 54:788-800.
9. van der Steeg WA, Holme I, Boekholdt SM, et al. High-density lipoprotein cholesterol, high-density lipoprotein particle size, and apolipoprotein A-I: significance for cardiovascular risk: The IDEAL and EPIC-Norfolk studies. J Am Coll Cardiol 2008; 51:634-642. This important post-hoc analysis of IDEAL and EPIC-Norfolk studies examined the relationship between HDL-cholesterol, HDL particle size and apoA-I, and incidence of CAD. The authors found that very high HDL-cholesterol and larger HDL particles may represent increased CAD risks. In contrast, apoA-I remained negatively associated with CAD risk in both studies.
10. Birjmohun RS, Dallinga-Thie GM, Kuivenhoven JA, et al. Apolipoprotein A-II is inversely associated with risk of future coronary artery disease. Circulation 2007; 116:2029-2035. In a nested case-control study (EPIC-Norfolk study), apoA-II was associated with a decreased risk of future CAD in apparently healthy people even after adjustment for apoA-I, HDL-cholesterol and HDL particle size. The findings imply that apoA-II may have a specific antiatherosclerotic effect.
11. Rader DJ, Ikewaki K, Duverger N, et al. Very low high-density lipoproteins without coronary atherosclerosis. Lancet 1993; 342:1455-1458.
12. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTER-HEART study): case-control study. Lancet 2004; 364:937-952.
13. Brown BG, Stukovsky KH, Zhao XQ. Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials. Curr Opin Lipidol 2006; 17:631-636.
14. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol 2006; 48:438-445.
15. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352:1425-1435.
16. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361:2005-2016.
17. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007; 357:1301-1310. In this post hoc analysis of the Treatment to New Targets (TNT) study, HDL-cholesterol levels remained a significant predictor of major cardiovascular events in statin-treated patients with low LDL-cholesterol levels.
18. Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006; 295:1556-1565. The authors examined the effect of very high-intensity statin therapy on the regression of coronary atherosclerosis. They found that rosuvastatin (40 mg/day) achieved a significant regression of atherosclerosis as assessed by IVUS measures of disease burden, supporting the use of high-dose statin in secondary cardiovascular prevention.
19. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended-release niacin on carotid intima-media thickness: ARBITER 3. Curr Med Res Opin 2006; 22:2243-2250.
20. Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation 2004; 110:3512-3517.
21. Keech A, Simes RJ, Barter P, 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 2005; 366:1849-1861.
22. Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370:1687-1697.
23. Hiukka A, Leinonen E, Jauhiainen M, et al. Long-term effects of fenofibrate on VLDL and HDL subspecies in participants with type 2 diabetes mellitus. Diabetologia 2007; 50:2067-2075. This subanalysis from FIELD showed no long-term effect of fenofibrate on HDL-cholesterol and apoA-I levels. Fenofibrate markedly shifted HDL subspecies towards smaller particles, implying a potential impact on HDL functionality.
24. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003; 290:2292-2300.
25. Tardif JC, Gregoire J, L'Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007; 297:1675-1682.
26. Tall AR, Yvan-Charvet L, Wang N. The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler Thromb Vasc Biol 2007; 27: 257-260.
27. Joy T, Hegele RA. Is raising HDL a futile strategy for atheroprotection? Nat Rev Drug Discov 2008; 7:143-155.
28. Vaisar T, Pennathur S, Green PS, et al. Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007; 117:746-756. This study investigated the biochemical composition of HDL isolated from healthy individuals and patients with CAD using shotgun proteomics. The findings suggest that HDL functionality extends to roles in the regulation of the complement system and tissue proteolysis.
29. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res 2005; 96:1221-1232.
30. Rader DJ. Mechanisms of disease: HDL metabolism as a target for novel therapies. Nat Clin Pract Cardiovasc Med 2007; 4:102-109. Provides useful updates on HDL metabolism and reverse cholesterol transport and their roles in CVD.
31. Barrett PH, Chan DC, Watts GF. Design and analysis of lipoprotein tracer kinetics studies in humans. J Lipid Res 2006; 47:1607-1619.
32. Rashid S, Patterson BW, Lewis GF. What have we learned about HDL metabolism from kinetics studies in humans? J Lipid Res 2006; 47:1631-1642.
33. Chan DC, Barrett PH, Watts GF. Recent studies of lipoprotein kinetics in the metabolic syndrome and related disorders. Curr Opin Lipidol 2006; 17:28-36.
34. Watts GF, Barrett PH, Ji J, et al. Differential regulation of lipoprotein kinetics by atorvastatin and fenofibrate in subjects with the metabolic syndrome. Diabetes 2003; 52:803-811.
35. Verges B, Petit JM, Duvillard L, et al. Adiponectin is an important determinant of apoA-I catabolism. Arterioscler Thromb Vasc Biol 2006; 26:1364-1369. First report of an association between low adiponectin and hypercatabolism of HDL-apoA-I in the metabolic syndrome.
36. Frenais R, Ouguerram K, Maugeais C, et al. High density lipoprotein apolipoprotein AI kinetics in NIDDM: a stable isotope study. Diabetologia 1997; 40:578-583.
37. Ji J, Watts GF, Johnson AG, et al. High-density lipoprotein (HDL) transport in the metabolic syndrome: application of a new model for HDL particle kinetics. J Clin Endocrinol Metab 2006; 91:973-979.
38. Ooi EM, Watts GF, Ji J, et al. Plasma phospholipid transfer protein activity, a determinant of HDL kinetics in vivo. Clin Endocrinol 2006; 65:752-759.
39. Asztalos BF, Roheim PS, Milani RL, et al. Distribution of apoA-I-containing HDL subpopulations in patients with coronary heart disease. Arterioscler Thromb Vasc Biol 2000; 20:2670-2676.
40. Syvanne M, Kahri J, Virtanen KS, Taskinen MR. HDLs containing apolipo-proteins A-I and A-II (LpA-I:A-II) as markers of coronary artery disease in men with noninsulin dependent diabetes mellitus. Circulation 1995; 92:364-370.
41. Voogt JN, Killion S, Awada M, et al. Measurement of cholesterol efflux, and global reverse cholesterol transport rates In vivo with stable isotopes. In: Atherosclerosis, Thrombosis, and Vascular Biology 8th Annual Meeting; 19-21 April 2007; Chicago, IL.
42. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10158 incident cases among 262525 participants in 29 western prospective studies. Circulation 2007; 115:450-458.
43. Bansal S, Buring JE, Rifai N, et al. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007; 298:309-316.
44. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA 2007; 298:299-308.
45. Rashid S, Watanabe T, Sakaue T, Lewis GF. Mechanisms of HDL lowering in insulin resistant, hypertriglyceridemic states: the combined effect of HDL triglyceride enrichment and elevated hepatic lipase activity. Clin Biochem 2003; 36:421-429.
46. Shachter NS. Apolipoproteins C-I and C-III as important modulators of lipoprotein metabolism. Curr Opin Lipidol 2001; 12:297-304.
47. Chan DC, Nguyen MN, Watts GF, Barrett PH. Plasma apolipoprotein C-III transport in centrally obese men: associations with very low-density lipoprotein apolipoprotein B and high-density lipoprotein apolipoprotein A-I metabolism. J Clin Endocrinol Metab 2008; 93:557-564. Recent data showing that elevated plasma apoC-III is an independent predictor of hypercatabolism of HDL-apoA-I in central obesity.
48. Adiels M, Taskinen MR, Packard C, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 2006; 49:755-765.
49. 1-triglycerides, as well as with postprandial lipemia.
50. Fabbrini E, Mohammed BS, Magkos F, et al. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 2008; 134:424-431.
51. Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and metabolic syndrome. Arterioscler Thromb Vasc Biol 2004; 24:29-33.
52. Ng TWK, Watts GF, Farvid MS, et al. Adipocytokines and VLDL metabolism: independent regulatory effects of adiponectin, insulin resistance, and fat compartments on VLDL apolipoprotein B-100 kinetics? Diabetes 2005; 54:795-802.
53. Cai L, de Beer MC, de Beer FC, van der Westhuyzen DR. Serum amyloid A is a ligand for scavenger receptor class B type I and inhibits high density lipoprotein binding and selective lipid uptake. J Biol Chem 2005; 280:2954-2961.
54. Anderson JL, Muhlestein JB, Horne BD, et al. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation 2000; 102:1227-1232.
55. Liao D, Tan H, Hui R, et al. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I protein synthesis and enhancing HDL cholesterol clearance. Circ Res 2006; 99:598-606. The authors found that hyperhomocysteine was associated with reduced apoA-I synthesis and enhanced HDL-cholesterol clearance in animal models.
56. Ng TWK, Watts GF, Barrett PH, et al. Effect of weight loss on LDL and HDL kinetics in the metabolic syndrome: associations with changes in plasma retinol-binding protein-4 and adiponectin levels. Diabetes Care 2007; 30:2945-2950. Weight loss significantly increased the catabolism of LDL-apoB and decreased both the catabolic and production rates of HDL-apoA-I. The decrease in HDL catabolism was associated with the rise in adiponectin levels with weight loss.
57. Chan DC, Watts GF, Nguyen MN, Barrett PH. Factorial study of the effect of n-3 fatty acid supplementation and atorvastatin on the kinetics of HDL apolipoproteins A-I and A-II in men with abdominal obesity. Am J Clin Nutr 2006; 84:37-43.
58. Nagashima K, Lopez C, Donovan D, et al. Effects of the PPAR gamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest 2005; 115:1323-1332.
59. Duez H, Lamarche B, Uffelman KD, et al. Dissociation between the insulin sensitizing effect of rosiglitazone and its effect on hepatic and intestinal lipoprotein production. J Clin Endocrinol Metab 2008; 93:1722-1729.
60. Lamon-Fava S, Diffenderfer MR, Barrett PH, et al. Effects of different doses of atorvastatin on human apolipoprotein B-100, B-48, and A-I metabolism. J Lipid Res 2007; 48:1746-1753.
61. Ooi EMM, Watts GF, Nestel PJ, et al. Dose-dependent regulation of high-density lipoprotein metabolism with rosuvastatin in the metabolic syndrome. J Clin Endocrinol Metab 2008; 93:430-437. Rosuvstatin dose-dependently increased plasma HDL-cholesterol and LpA-I concentrations by reducing LpA-I fractional catabolism.
62. Sviridov D, Hoang A, Ooi EEM, et al. Indices of reverse cholesterol transport in subjects with metabolic syndrome after treatment with rosuvastatin. Atherosclerosis 2008; 197:732-739. This study found that rosuvastatin (40 mg/day) reduced in-vitro cholesterol efflux activity in patients with MetS. These findings suggest that patients with high CVD risk may not necessarily derive incremental benefit from higher dose rosuvastatin with regard to reverse cholesterol transport.
63. Brousseau ME, Diffenderfer MR, Millar JS, et al. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol 2005; 25:1057-1064.
64. Chapman MJ. How does nicotinic acid modify the lipid profile? Eur Heart J Suppl 2006; 8:F54-F59.
65. Grundy SM, Mok HY, Zech L, Berman M. Influence of nicotinic acid on metabolism of cholesterol and triglycerides in man. J Lipid Res 1981; 22:24-36.
66. Packard CJ, Stewart JM, Third JLHC, et al. Effects of nicotinic acid therapy on high-density lipoprotein metabolism in type II and type IV hyperlipoproteinaemia. Biochim Biophys Acta 1980; 618:53-62.
67. Shepherd J, Packard CJ, Patsch JR, et al. Effects of nicotinic acid therapy on plasma high density lipoprotein subfraction distribution and composition and on apolipoprotein A metabolism. J Clin Invest 1979; 63:858-867.
68. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006; 58:389-462.
69. Duffy D, Rader DJ. Emerging therapies targeting high-density lipoprotein metabolism and reverse cholesterol transport. Circulation 2006; 113:1140-1150.
70. Sprecher DL, Massien C, Pearce G, et al. Triglyceride: high-density lipoprotein cholesterol effects in healthy subjects administered a peroxisome proliferator activated receptor {delta} agonist. Arterioscler Thromb Vasc Biol 2007; 27:359-365. The authors examined the mechanism of action of a selective PPAR-d agonist on lipoprotein metabolism. Treatment with GW501516 improved dyslipidemia possibly because of enhanced skeletal muscle fatty acid oxidation and upregulation of ABCA1 expression.
71. Krishna R, Anderson MS, Bergman AJ, et al. Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies. Lancet 2007; 370:1907-1914. The authors reported the potent raising effect of a new CETP inhibitor on HDL-choleserol. Unlike tocetrapib, the use of anacetrapib did not significantly alter 24-h ambulatory blood pressure. This finding supports the notion that the negative effects of torcetrapib may be related to a specific, off-target effect of the drug on blood pressure.
72. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Diabetes Care 2007; 30:162-172.