Effect of niacin monotherapy on high density lipoprotein composition and function

Scott M. Gordon,Marcelo J. Amar,Nehal N. Mehta,Kianoush Jeiran,Martin P. Playford,Emma Staller,Michael Stagliano,Tomas Vaisar,Alan T. Remaley

doi:10.1186/s12944-020-01350-3

Abstract

BackgroundNiacin has modest but overall favorable effects on plasma lipids by increasing high density lipoprotein cholesterol (HDL-C) and lowering triglycerides. Clinical trials, however, evaluating niacin therapy for prevention of cardiovascular outcomes have returned mixed results. Recent evidence suggests that the HDL proteome may be a better indicator of HDL’s cardioprotective function than HDL-C. The objective of this study was to evaluate the effect of niacin monotherapy on HDL protein composition and function.MethodsA 20-week investigational study was performed with 11 participants receiving extended-release niacin (target dose = 2 g/day) for 16-weeks followed by a 4-week washout period. HDL was isolated from participants at weeks: 0, 16, and 20. The HDL proteome was analyzed at each time point by mass spectrometry and relative protein quantification was performed by label-free precursor ion intensity measurement.ResultsIn this cohort, niacin therapy had typical effects on routine clinical lipids (HDL-C + 16%, q < 0.01; LDL-C − 20%, q < 0.01; and triglyceride − 15%, q = 0.1). HDL proteomics revealed significant effects of niacin on 5 proteins: serum amyloid A (SAA), angiotensinogen (AGT), apolipoprotein A-II (APOA2), clusterin (CLUS), and apolipoprotein L1 (APOL1). SAA was the most prominently affected protein, increasing 3-fold in response to niacin (q = 0.008). Cholesterol efflux capacity was not significantly affected by niacin compared to baseline, however, stopping niacin resulted in a 9% increase in efflux (q < 0.05). Niacin did not impact HDL’s ability to influence endothelial function.ConclusionExtended-release niacin therapy, in the absence of other lipid-modifying medications, can increase HDL-associated SAA, an acute phase protein associated with HDL dysfunction.

Highlights

Niacin has modest but overall favorable effects on plasma lipids by increasing high density lipoprotein cholesterol (HDL-C) and lowering triglycerides
The decrease in total cholesterol resulted from a 20% reduction in low-density lipoprotein cholesterol (LDL-C) (q < 0.01; Fig. 2b) and a 16% increase of HDL-C (q < 0.01; Fig. 2c)
HDL particle number did not change with niacin (Fig. 2g), HDL particle size increased by 7% (q < 0.01; Fig. 2j) likely reflecting the increased cholesterol content in the core of the particle

Summary

Introduction

Niacin has modest but overall favorable effects on plasma lipids by increasing high density lipoprotein cholesterol (HDL-C) and lowering triglycerides. Several trials evaluating cholesterol ester transfer protein (CETP) inhibitors have failed to reduce clinical events [3]. These results have called into question the relevance of HDL’s cholesterol content in the ability to protect against CVD and have helped the field to understand the distinction between HDL-C and HDL function. While HDL is generally thought of as protective, there is a growing body of literature that supports the existence of dysfunctional or proinflammatory HDL These particles are generated under systemic inflammatory conditions and have impaired capacity for cholesterol efflux and reverse cholesterol transport, important atheroprotective functions of HDL that have been associated with reduced CVD events [9]. The impaired functionality of these particles is driven by replacement of the core HDL protein apolipoprotein A-I (apoA-I) with the acute phase protein serum amyloid A (SAA)

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