Niacin: an old lipid drug in a new NAD+ dress

Abstract

Niacin, the first antidyslipidemic drug, has been at the center stage of lipid research for many decades before the discovery of statins. However, to date, despite its remarkable effects on lipid profiles, the clinical outcomes of niacin treatment on cardiac events is still debated. In addition to its historically well-defined interactions with central players of lipid metabolism, niacin can be processed by eukaryotic cells to synthesize a crucial cofactor, NAD⁺ NAD⁺ acts as a cofactor in key cellular processes, including oxidative phosphorylation, glycolysis, and DNA repair. More recently, evidence has emerged that NAD⁺ also is an essential cosubstrate for the sirtuin family of protein deacylases and thereby has an impact on a wide range of cellular processes, most notably mitochondrial homeostasis, energy homeostasis, and lipid metabolism. NAD⁺ achieves these remarkable effects through sirtuin-mediated deacetylation of key transcriptional regulators, such as peroxisome proliferator-activated receptor gamma coactivator 1-α, LXR, and SREBPs, that control these cellular processes. Here, we present an alternative point of view to explain niacin's mechanism of action, with a strong focus on the importance of how this old drug acts as a control switch of NAD⁺/sirtuin-mediated control of metabolism.

Keywords: HDL; LDL; cholesterol; dyslipidemia; fatty acid oxidation; kidney disease; lipid synthesis; mitochondria; nicotinic acid; sirtuins.

Graphical abstract

Fig. 1.

Known mechanisms of action of niacin. Niacin increases circulating HDL particles for peripheral cholesterol scavenging by two described mechanisms: First, by reducing the surface expression of the hepatic HDL receptor β-ATP synthase, which is involved in the endocytosis of HDL particles in the liver, and, second, by increasing the expression of ABCA1, which promotes ApoA-I lipidation and stabilization and thus promotes HDL production. Moreover, niacin reduces the activity of DGAT, which leads to reduced TG synthesis, Apo B degradation, and reduced VLDL and LDL production and circulation.

Fig. 2.

Pathways modulating NAD⁺ levels in mammals. NAD⁺ can be synthesized either via salvage pathways from precursors such as niacin (nicotinic acid), nicotinamide (NAM), and nicotinamide riboside (NR) or de novo from tryptophan (Trp). In the first step of the Preiss-Handler pathway, niacin is converted into NA mononucleotide (NAMN) by nicotinate phosphoribosyltransferase (NAPRT). NAM mononucleotide adenylyltransferase (NMNAT) uses NAMN to generate NA adenine dinucleotide (NAAD), which gets converted into NAD⁺ by NAD synthetase (NADS). NAD⁺ synthesis from NAM and NR comprises their conversion into NAM mononucleotide (NMN) by NAM phosphoribosyltransferase (NAMPT) and NAM riboside kinase (NRK), respectively, and the subsequent conversion of NMN into NAD⁺ by NMNAT. NMN can also be recycled back into NR by CD73. The de novo NAD⁺ synthesis pathway from Trp consists of eight steps and merges with the Preiss-Handler pathway. Pathways that reduce NAD⁺ availability include the conversion of NAM into methylnicotinamide (MNA) by N-methyltransferase (NNMT) and NAD⁺ consumption by enzymes including the sirtuins, CD38, and PARP1.

Fig. 3.

Niacin’s mechanism of action explained by raising NAD⁺ levels? As a precursor for NAD⁺, niacin can activate the deacylase SIRT1, which might explain niacin’s beneficial effects on lipid homeostasis. First, SIRT1 activates PGC-1α, which leads to increased mitochondrial activity and FA oxidation. Moreover, SIRT1 activates LXR, which leads to increased expression of ABCA1, and thus increased circulating HDL particles. Furthermore, SIRT1 destabilizes SREBPs and thereby lowers SREBP-mediated FA, TG, and cholesterol synthesis and circulation.