Abstract
AimNicotinic acid (NA) treatment decreases plasma triglycerides and increases HDL cholesterol, but the mechanisms involved in these change are not fully understood. A reduction in cholesteryl ester transfer protein (CETP) activity has been advanced to explain most lipid-modulating effects of NA. However, due to the central role of CETP in reverse cholesterol transport in humans, other effects of NA may have been hidden. As dogs have no CETP activity, we conducted this study to examine the specific effects of extended-release niacin (NA) on lipids and high-density lipoprotein (HDL) cholesteryl ester (CE) turnover in obese Insulin-Resistant dogs with increase plasma triglycerides.MethodsHDL kinetics were assessed in fasting dogs before and four weeks after NA treatment through endogenous labeling of cholesterol and apolipoprotein AI by simultaneous infusion of [1,2 13C2] acetate and [5,5,5 2H3] leucine for 8 h. Kinetic data were analyzed by compartmental modeling. In vitro cell cholesterol efflux of serum from NA-treated dogs was also measured.ResultsNA reduced plasma total cholesterol, low-density lipoprotein cholesterol, HDL cholesterol, triglycerides (TG), and very-low-density lipoprotein TG concentrations (p < 0.05). The kinetic study also showed a higher cholesterol esterification rate (p < 0.05). HDL-CE turnover was accelerated (p < 0.05) via HDL removal through endocytosis and selective CE uptake (p < 0.05). We measured an elevated in vitro cell cholesterol efflux (p < 0.05) with NA treatment in accordance with a higher cholesterol esterification.ConclusionNA decreased HDL cholesterol but promoted cholesterol efflux and esterification, leading to improved reverse cholesterol transport. These results highlight the CETP-independent effects of NA in changes of plasma lipid profile.
Highlights
The lipid-modulating effects of nicotinic acid (NA) were reported almost 50 years ago [1]
Various mechanisms have been reported to explain this high-density lipoprotein (HDL)-C increase with NA in humans, including enhancement of apolipoprotein AI production but with no change in its fractional catabolic rate [4]; reduction of HDL uptake with no change in cholesteryl ester (CE) uptake, measured in vitro [5]; and a reduction of plasma cholesteryl ester transfer protein (CETP) activity, which allows the transfer of TG and CE between HDL and lower density lipoproteins [6,7]
In vitro studies have shown that NA stimulates other pathways involved in HDL metabolism, such as the expression of ATP binding cassette A1 (ABCA1) [8] and peroxisome proliferator-activated receptor (PPAR) γ [9,10], but has no effect on HDL binding, CE selective uptake, or the expression of scavenger receptor class B type 1 (SR-BI) in CHO cells [11]
Summary
The lipid-modulating effects of nicotinic acid (NA) were reported almost 50 years ago [1]. Various mechanisms have been reported to explain this HDL-C increase with NA in humans, including enhancement of apolipoprotein AI (apoAI) production but with no change in its fractional catabolic rate [4]; reduction of HDL uptake with no change in cholesteryl ester (CE) uptake, measured in vitro [5]; and a reduction of plasma cholesteryl ester transfer protein (CETP) activity, which allows the transfer of TG and CE between HDL and lower density lipoproteins [6,7]. The ability of NA treatment to increase HDL in humans has not been replicated in animal models. NA treatment affected HDL concentration in transgenic mice expressing human CETP, but not in wild type animals naturally with no CETP activity [7], underlining the key role of this transfer protein
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