doi: 10.1161/ATVBAHA.108.175224
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© 2008 American Heart Association, Inc.
Editorials |
Of Mice and Men
Blowing Away the Cobwebs From the Mechanism of Action of Niacin on HDL Metabolism
From the Metabolic Research Centre, School of Medicine and Pharmacology, University of Western Australia, Perth, Australia.
Correspondence to Professor Gerald F. Watts, School of Medicine and Pharmacology, University of Western Australia, Royal Perth Hospital, Australia. E-mail gerald.watts{at}uwa.edu.au
IAn increasing body of evidence suggests that disturbed HDL metabolism increases the risk of cardiovascular disease (CVD).1 HDL metabolism is central to reverse cholesterol transport (RCT), in which excess cholesterol from peripheral tissue is returned to the liver for extracorporeal elimination. HDLs also have non-RCT functions including antiinflammatory, antioxidant, and antithrombotic properties. These may relate collectively to the apoA-I content of HDL particles. A number of therapeutic approaches that target HDL metabolism may be useful in preventing and regressing atherosclerosis and coronary disease.2–3
See accompanying article on page 2016
Among lipid-regulators, niacin (nicotinic acid, vitamin B3, pyridine-3-carboxylic acid) is the most effective therapeutic agent presently available for elevating HDL-cholesterol and apoA-I. Notwithstanding issues with tolerability, niacin has long been available for treating atherogenic dyslipidemias. Data from several clinical trials collectively demonstrate that niacin alone or in combination with other agents, including statins, can reduce cardiovascular events and progression of coronary atherosclerosis.4 The precise therapeutic mechanism(s) of action of niacin remains unclear, but may largely involve a favorable regulation of HDL metabolism. But exactly how it mediates this effect has not yet been elucidated.
In this issue of Atherosclerosis, Thrombosis and Vascular Biology, van der Hoorn et al present data in a new animal model on the mechanism of the effect of niacin on HDL metabolism.5 First, they demonstrated that niacin increased plasma HDL-cholesterol concentration in the APOE*3Leiden.CETP (E3L.CETP) mouse model (ie, E3L mice crossbred with human CETP-expressing mice) but not in the E3L model alone. Second, in a matched study design they showed in E3L.CETP mice on a Western-type diet that niacin (118 mg/kg/d, 360 mg/kg/d and 1180 mg/kg/d for at least 3 weeks) dose-dependently increased plasma HDL-cholesterol and apoA-I concentrations by several mechanisms involving reductions in plasma VLDL-triglyceride concentrations and in the expression, activity, and mass of CETP; there was also a non–dose-dependent reduction in hepatic lipase activity. Using exogenously radiolabeled 125I-apoA-I and monoexponential analysis, they reported that niacin dose-dependently decreased the clearance of apoA-I from plasma (associated with reduced uptake by the kidney), but did not alter the hepatic secretion of apoA-I nor the biliary and fecal excretion of cholesterol. With high dose of niacin (1180 mg/kg/d), the decrease in plasma triglycerides (+77%) was associated with a commensurate increase in the residence time of HDL-apoA-I (+89%). The kinetic findings generally concur with previous in vitro studies in HepG-2 cells, and suggest that the main mechanism for the elevation in plasma apoA-I concentration with niacin involves decreased clearance of apoA-I related to a primary reduction in the expression and activity of CETP.6
These data from van der Hoorn et al have to be placed within the context of the complexity of the bioregulation of the HDL system. The authors postulated that by inhibiting the hormone-sensitive lipase via the niacin receptor GPR109A in adipose tissue, niacin decreases triglyceride lipolysis and thereby the release of free fatty acid (FFA) from adipocytes. The decreased flux of FFA to the liver could inhibit triglyceride synthesis and subsequent hepatic secretion of larger size VLDLs. Consistent with previous studies, they suggested that the increase in HDL-cholesterol may be a consequence of reduction in the pool of plasma VLDL (the acceptor of CETP-mediated HDL-CE transfer) that is available for the heteroexchange of neutral lipids (cholesterol and triglycerides) under the action of CETP. Their demonstration in this animal model that hepatic lipase activity was inhibited by niacin could also contribute to the formation of larger, CE enriched HDL particles that are cleared more slowly from the circulation. However, these postulates have to be weighted against the lack of data presented on the kinetics of both FFA and VLDL. Beyond the impact of the therapeutic decrease in triglyceride substrate on CETP activity, the reduction in hepatic cholesterol content with niacin reported in the present study could also decrease the hepatic expression of CETP via a liver X receptor (LXR) response element on the CETP promotor.7 However, in other studies, niacin has not been found to decrease plasma CETP activity.8 Moreover, recent data indicate that niacin may directly inhibit hepatocyte diacylglycerol acyltransferase-2 (DGAT-2), a key enzyme in triglyceride synthesis.9 There is also good evidence that in HepG-2 cells, niacin retards the hepatic catabolism of apoA-I via the "HDL holoparticle catabolism receptor" pathway and not by the SRB1 pathway,10 consistent with the absence of effect of niacin on expression of SR-B1 in the study by van der Hoorn et al.5 The precise role that the renal cubulin-megalin receptor complex plays in the mechanism of niacin in delaying the clearance of apoA-I from plasma remains to be investigated.
Mouse models have been used widely to evaluate the impact of therapies on atherosclerosis and lipoprotein metabolism. Why did the authors use the E3L.CETP mouse model? First, by inserting the human CETP transgene, they could investigate, as in another mouse model,11 whether CETP modulates the effect of niacin on HDL metabolism. Second, unlike the APOE–/– and LDLr–/– models which exhibit extremely elevated plasma cholesterol concentration on a high-fat diet (>25 mmol/L), the E3L.CETP mouse tends to simulate a more human-like lipoprotein profile (plasma triglyceride 
3 mmol/L and cholesterol 12 mmol/L) and may be more sensitive to lipid-lowering therapies.12 However, genetic-manipulated mouse models do not strictly reflect the physiology nor pathophysiology of human lipid and lipoprotein metabolism.
It should also be noted that the doses of niacin used in the present and in another experimental study are substantially higher than those used clinically in treating human dyslipidemias (1 to 2 g/d), potentially limiting the translational value of the data.5,11 The authors argued that the experimental doses are clinically relevant because of the higher metabolic rate of mice (5 to 10 times) compared with humans. The validity of this claim is, however, questionable in the absence of data on the comparative pharmacokinetics of niacin.
How do the findings by van der Hoon et al compare with kinetic studies in humans? Using exogenously radiolabeled 125I-apoA-I, in normolipidaemic subjects 3-week treatment with niacin (3 g/d) has been shown to increase plasma apoA-I by decreasing its catabolism.13,14 However, a recent endogeneously labeling isotope study by Lamon-Fava et al reported that in men with combined hyperlipidemia featuring low HDL-cholesterol at baseline, 12-week treatment with niacin (2 g/d) significantly increases HDL-apoA-I concentration by increasing the production of apoA-I.8 Discrepancies among the aforementioned studies might be attributable to different experimental models, subject characteristics (gender and baseline HDL-cholesterol) and study design (dose and duration of treatment), modeling of the data (monoexponential versus multicompartmental analyses), and study protocols (radiolabeling versus stable isotopic techniques).
Reverse cholesterol transport is a major mechanism by which HDL protects against atherosclerosis. The present data did not find a significant effect of niacin on biliary and fecal cholesterol excretion. This suggests that niacin treatment may not elicit a net extracorporeal flux of cholesterol, despite significantly increasing plasma HDL-cholesterol and apoA-I concentrations. This notion needs further investigation. Voogt et al recently described a novel stable isotope method for assessing cholesterol efflux and transport from tissues in humans (see deGoma et al2) and application of this test, and other pertinent measures of HDL functionality, to the effects of niacin would be of interest.
The efficacy of niacin in correcting atherogenic dyslipidemia does not only depend on its impact on HDL, but also on the simultaneous reduction in triglycerides, LDL-cholesterol, apoB and Lp(a) concentrations. Further investigation of the integrated mechanism of action of niacin on human lipoprotein transport is warranted, given divergent data on the effect of this agent on the secretion and clearance of VLDL.5,15,16 Beyond lifestyle modifications, niacin is potentially the most clinical useful agent in treating atherogenic dyslipidemia in subjects with insulin resistance syndrome. The Figure shows how VLDL and HDL transport is perturbed by insulin resistance and how niacin may potentially correct these abnormalities. Hypertriglyceridemia and low HDL-apoA-I in insulin resistance may be caused by a combination of overproduction of VLDL-apoB-100, decreased catabolism of VLDL-apoB-100, and increased catabolism of HDL-apoA-I particles (Figure 1b). These abnormalities may be consequent on a global metabolic effect of insulin resistance that increases the flux of FFA from adipose tissue to the liver, the accumulation of fat in the liver, increased hepatic secretion of triglycerides, and remodeling and overcatabolism of HDL particles in the circulation. Based on the findings of van de Hoorn et al, and on recent data from in vitro and human studies, niacin may correct abnormalities in this system by inhibiting triglyceride lipolysis and subsequent hepatic triglyceride synthesis for VLDL production, as well as by increasing the production of apoA-I and decreasing CETP-mediated heteroexchange of neutral lipid between HDL and VLDL that slows the clearance of HDL-apoA-I (figure 1C). As we have argued elsewhere,17 however, the optimal antiatherogenic effect of a given therapeutic agent on HDL metabolism may be to increase HDL-apoA-I transport and concentration with unchanged or increased catabolism, reflecting an accelerated rate of RCT.
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indicates increase; 
, decrease. The relative extent to which liver and kidney contributed to the catabolism of HDL-apoA-I remains unclear.
Niacin treatment is likely to be most frequently used in combination with statins. However, the kinetic effect of this combination on HDL metabolism in MetS has not yet been investigated. Niacin added to a statin increase the concentration of larger size 
1-HDL and this may be associated with less progression of coronary atherosclerosis.18 Whether niacin alone or in combination with statins decreases cardiovascular events awaits further confirmation in the ongoing AIM-HIGH and HPS-THRIVE trials.4 Direct competitive inhibitors of CETP elevate HDL to a greater extent than niacin, but their clinical use has been seriously questioned by the ILLUMINATE study.19 However, this may relate to a specific, off-target pressor effect of torcetrapib that is not a feature of other direct CETP inhibitors.20 Niacin does not per se elevate blood pressure, but like CETP inhibitors delays the clearance of HDL-apoA-I.21 Finally, the clinical success of niacin as a treatment for dyslipidemia and atherosclerosis also depends on use of preparations, such as extended release forms with or without a prostaglandin (PG) D2 (PGD2) receptor antagonist (laropiprant), that significantly but do not totally diminish the risk of flushing, an end point that was not reported in the E3L.CETP mouse model!5
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Acknowledgments |
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Disclosures
D.C.C. is an National Health and Medical Research Foundation (NHMRC) Career Development Fellow.
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Arterioscler. Thromb. Vasc. Biol. 2008 28: 2016-2022.
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