Effects of extended-release niacin on lipoprotein subclass distribution

Morgan, John; Capuzzi, David M.; Baksh, Ronnie I; Intenzo, Charles; Carey, Christina; Reese, Dana; Walker, Kalen

doi:10.1016/s0002-9149(03)00394-1

Cited by 101 publications

(56 citation statements)

References 15 publications

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“…Meta-analysis of 30 randomized controlled trials reveals that niacin increases HDL-C on average by 16%; in parallel, niacin decreases plasma TG typically by 20% (Birjmohun et al, 2005). The action of niacin results in elevated plasma levels of both large and small HDL (McKenney et al, 2001;Morgan et al, 2003). In addition, niacin favorably modifies HDL composition, preferentially increasing apoA-I in the form of large HDL2-like, CE-rich particles (Sakai et al, 2001;Morgan et al, 2003).…”

Section: Defective Small Dense Hdl: New Therapeutic Targetmentioning

confidence: 99%

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

Kontush¹,

Chapman²

2006

Pharmacol Rev

659

594

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Section: Defective Small Dense Hdl: New Therapeutic Targetmentioning

confidence: 99%

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

Kontush¹,

Chapman²

2006

Pharmacol Rev

659

594

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“…Elevated plasma levels of LDL, particularly sdLDL, are the major risk factor and a likely causative agent of atherosclerosis (23)(24)(25). Conventional lipid-lowering therapies (including statins, fi brates, niacin, and their combinations) not only improve the overall plasma levels of lipoproteins but also decrease the proportion of sdLDL and thereby increase the median size of LDL ( 43,(53)(54)(55)(56)(57)(58)(59). The results in Fig.…”

Section: Effect Of the Particle Size On Ldl Fusion: Potential Metabolmentioning

confidence: 99%

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Gantz

Herscovitz

et al. 2012

Journal of Lipid Research

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of LDL cholesterol and, particularly, apoB are the strongest predictors of atherosclerosis and its causative agents ( 3 ). In atherosclerosis, LDL lipids are deposited in the arterial intima; according to the response-to-retention paradigm ( 4, 5 ), LDL retention by the arterial matrix proteoglycans triggers a cascade of pro-atherogenic events culminating in formation of atherosclerotic plaque ( 6-8 ). These events include biochemical modifi cations of LDL, such as oxidation and/or hydrolysis by the resident proteases and lipases, e.g., phospholipase A 2 and sphingomyelinase, which can reduce LDL affi nity for the LDL receptor, increase LDL affi nity for the proteoglycans, and promote LDL fusion (7)(8)(9)(10)(11)(12)(13)(14). In addition, ionic interactions with proteoglycans reduce LDL stability and promote their fusion and rupture (i.e., release of core lipids) ( 15 ). Fusion of lipoproteins prevents their exit from the arterial intima and thereby augments their further modifi cations, enhances LDL uptake by the arterial macrophages, and initiates the formation of atherosclerotic lesions ( 9, 16 ). Therefore, the pro-atherogenic potential of LDL is thought to be linked to their ability to fuse ( 9,10,17 ). Dissecting the pathogenic pathway of LDL fusion and identifying key factors that promote or inhibit this pathway can help obtain new therapeutic targets for atherosclerosis.Structural analysis of intact and modifi ed LDL has been limited to low resolution ( у 16 Å) by the large size and hydrophobicity of apoB and by LDL heterogeneity ( 1,(18)(19)(20)(21). Human plasma LDL consist of subclasses differing Abstract Fusion of modifi ed LDL in the arterial wall promotes atherogenesis. Earlier we showed that thermal denaturation mimics LDL remodeling and fusion, and revealed kinetic origin of LDL stability. Here we report the fi rst quantitative analysis of LDL thermal stability. Turbidity data show sigmoidal kinetics of LDL heat denaturation, which is unique among lipoproteins, suggesting that fusion is preceded by other structural changes. High activation energy of denaturation, E a = 100 ± 8 kcal/mol, indicates disruption of extensive packing interactions in LDL. Size-exclusion chromatography, nondenaturing gel electrophoresis, and negativestain electron microscopy suggest that LDL dimerization is an early step in thermally induced fusion. Monoclonal antibody binding suggests possible involvement of apoB N-terminal domain in early stages of LDL fusion. LDL fusion accelerates at pH < 7, which may contribute to LDL retention in acidic atherosclerotic lesions. Fusion also accelerates upon increasing LDL concentration in near-physiologic range, which likely contributes to atherogenesis. Thermal stability of LDL decreases with increasing particle size, indicating that the pro-atherogenic properties of small dense LDL do not result from their enhanced fusion. Our work provides the fi rst kinetic approach to measuring LDL stability and suggests that lipid-lowering therapies that reduce LDL concentration but increase t...

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“…Several studies have confirmed this observation in patients with different types of dyslipidemia treated with 2, 3, or 4 g/day of regular or ER niacin (Johansson and Carlson 1990;Knopp et al 1998;Morgan et al 2003;Wahlberg et al 1990) and in patients with coronary artery disease (Kuvin et al 2006). A very recent study showed that also 1 g/day of ER niacin increases large HDL particles in dyslipidemic patients, with a concomitant significant increase in mean HDL size (Franceschini et al 2013).…”

Section: Niacinmentioning

confidence: 81%

Effects of Established Hypolipidemic Drugs on HDL Concentration, Subclass Distribution, and Function

Gomaraschi

Adorni

Banach

et al. 2014

Handbook of Experimental Pharmacology

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Effects of extended-release niacin on lipoprotein subclass distribution

Cited by 101 publications

References 15 publications

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis

Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis

Effects of Established Hypolipidemic Drugs on HDL Concentration, Subclass Distribution, and Function

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