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Niacin and cholesterol: role in cardiovascular disease (review)

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Abstract

Niacin has been widely used as a pharmacologic agent to regulate abnormalities in plasma lipid and lipoprotein metabolism and in the treatment of atherosclerotic cardiovascular disease. Although the use of niacin in the treatment of dyslipidemia has been reported as early as 1955, only recent studies have yielded an understanding about the cellular and molecular mechanism of action of niacin on lipid and lipoprotein metabolism. In brief, the beneficial effect of niacin to reduce triglycerides and apolipoprotein-B containing lipoproteins (e.g., VLDL and LDL) are mainly through: a) decreasing fatty acid mobilization from adipose tissue triglyceride stores, and b) inhibiting hepatocyte diacylglycerol acyltransferase and triglyceride synthesis leading to increased intracellular apo B degradation and subsequent decreased secretion of VLDL and LDL particles. The mechanism of action of niacin to raise HDL is by decreasing the fractional catabolic rate of HDL-apo AI without affecting the synthetic rates. Additionally, niacin selectively increases the plasma levels of Lp-AI (HDL subfraction without apo AII), a cardioprotective subfraction of HDL in patients with low HDL. Using human hepatocytes (Hep G2 cells) as an in vitro model system, recent studies indicate that niacin selectively inhibits the uptake/removal of HDL-apo AI (but not HDL-cholesterol ester) by hepatocytes, thereby increasing the capacity of retained HDL-apo AI to augment cholesterol efflux through reverse cholesterol transport pathway. The studies discussed in this review provide evidence to extend the role of niacin as a lipid-lowering drug beyond its role as a vitamin.

Section snippets

Background

Nicotinic acid (Niacin, Vitamin B3) is a water soluble vitamin. The major metabolic role of niacin is that it serves as a precursor for two essential coenzymes, Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). Both NAD and NADP can be reduced to NADH and NADPH, respectively, and these coenzymes participate in oxidation-reduction reactions catalyzed by dehydrogenase and oxidoreductase enzymes. These NAD/NADP linked enzyme systems are involved in

Lipid profile and CHD

Disorders in lipid (e.g., cholesterol and triglycerides) and lipoprotein metabolism are major established independent risk factors in the development and progression of atherosclerotic CHD. Lipid-carrying proteins, termed as lipoproteins, are classified as 3 major classes, including very low density lipoprotein (VLDL), low density lipoprotein (LDL), and high density lipoprotein (HDL). VLDL carries mainly triglycerides, and cholesterol is carried mainly in LDL, and to a lesser extent in HDL

Niacin as a lipid-regulating agent and its effect on atherosclerotic CHD

The use of niacin as a pharmacologic agent has been reported as early as 1955 by Altshul, Hoffer and Stephen [23], and currently it is a widely used agent in the treatment of dyslipidemia [24], [25]. In pharmacologic doses (1-3 g/day), niacin reduces concentrations of total plasma cholesterol, apolipoprotein (apo) B, triglyceride, VLDL, LDL, and Lp(a), and increases HDL levels (reviewed in 25). Niacin is the most potent available lipid-regulating agent to increase HDL levels. Because of these

Mechanism of action of niacin on triglyceride and apo B metabolism

There are mainly two mechanisms by which niacin influences plasma lipids and the secretion of apo B bearing lipoproteins including VLDL particles in the liver. VLDL is precursor to subsequent catabolic products including VLDL remnants, intermediate density lipoproteins (IDL), and LDL. Lp(a) is essentially LDL with a polypeptide linkage of apo B to apo(a). These include: 1) modulation of triglyceride lipolysis in adipose tissue, and 2) modulation of triglyceride synthesis resulting in increased

Role of niacin in HDL metabolism

As discussed earlier, niacin is the most effective pharmacologic agent to increase HDL levels. HDL are a complex class of lipoproteins with hydrophobic core of cholesterol esters and triglycerides and an outer hydrophilic layer of apolipoproteins, phospholipids and unesterified cholesterol. Apo AI and apo AII are the major proteins of HDL (accounting for approximately 70% and 20% of protein mass respectively). The liver and intestine are major organs for synthesis and secretion of HDL and its

Conclusions

A brief outline of the mechanisms of action of niacin on triglyceride, VLDL/LDL, and HDL metabolic processes is shown in Fig. 1. The ability of niacin to reduce triglyceride and VLDL/LDL secretion may involve modulation of specific events in adipocytes and hepatocytes. Firstly, niacin can decrease the mobilization of fatty acids from adipose tissue by inhibiting the hormone-sensitive lipase-mediated lipolysis of triglycerides. Secondly, niacin by directly inhibiting hepatic microsomal

Acknowledgements

This work has been supported, in part, by Veterans Affairs Merit Review Program, The Southern California Institute for Education and Research, and Kos Pharmaceuticals.

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