Effects of Nicotinic Acid and its Derivatives on Lipid Metabolism and Other Metabolic Factors Related to Atherosclerosis

Walldius, G; Wahlberg, Gustaf

doi:10.1007/978-1-4613-2459-1_22

Cited by 9 publications

(7 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition to its function as a vitamin, nicotinic acid (NA; or niacin) has been used as a lipid-lowering drug for more than four decades (1, 2); NA treatment, at high doses, decreases LDL-cholesterol, triglycerides, and VLDL while increasing HDL-cholesterol (3, 4), and all of these effects are beneficial to the prevention of atherosclerosis. The lipid-lowering effects of NA have been traditionally attributed to its antilipolytic effect in adipocytes (5); NA binds to and stimulates a G-protein coupled receptor (i.e., NA receptor) in the plasma membrane of adipocytes to decrease cAMP and lipolysis, and decreased lipolysis in adipocytes reduces the supply of FFA for triglyceride synthesis and VLDL formation in the liver.…”

Section: Introductionmentioning

confidence: 99%

Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment

Choi

Yoon

et al. 2011

Metabolism

View full text Add to dashboard Cite

Nicotinic acid (NA; or niacin) has been used as a hypolipidemic agent for more than four decades. However, the mechanisms underlying the effects of NA treatment (wanted and unwanted) are still poorly understood. In the present study, we discovered that NA infusion in rats resulted in dephosphorylation (i.e., activation) of the forkhead transcription factor FOXO1 in insulin sensitive tissues such as skeletal and cardiac muscles, liver, and adipose tissue. These NA effects were opposite to the effects of insulin to increase FOXO1 phosphorylation. To test whether NA alters gene expression in these tissues, rats were infused for 7 h with NA (30 μmol/h) and/or insulin (5 mU/kg/min), and gene expression was evaluated using a microarray analysis. NA had widespread effects on gene expression in all of the tissues studied, and the number of genes affected by NA greatly exceeded that of genes affected by insulin. A systematic (or strategic) analysis of the microarray data revealed that there were numerous genes whose expression was regulated inversely by insulin and NA in correlation with FOXO1 phosphorylation, representing potential FOXO1 target genes. We also identified a group of genes whose expression was altered by NA exclusively in adipose tissue, presumably due to stimulation of the NA receptor in this tissue. Finally, there were genes whose expression was altered by both NA and insulin, likely via lowering plasma FFA levels, including lipoprotein lipase and ATP-binding cassette A1 which play a major role in the regulation of circulating lipids. Thus, our data suggest that NA alters gene expression in insulin-sensitive tissues by various mechanisms. Some of the NA-induced changes in gene expression are discussed as potential mechanisms underlying wanted and unwanted effects of NA treatment.

show abstract

Section: Introductionmentioning

confidence: 99%

Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment

Choi

Yoon

et al. 2011

Metabolism

View full text Add to dashboard Cite

show abstract

“…NA binds to and stimulates a G proteincoupled receptor [i.e., GPR109A or HM74A (37,41)] in the plasma membrane of adipocytes to decrease cAMP and lipolysis, which in turn reduces the plasma levels of FFA, substrates for hepatic TG synthesis, and VLDL formation. However, this classic view may need revision, because circulating FFA levels, which initially decrease during treatment, rebound after long-term NA treatment (see below), whereas its lipid-lowering effects persist (38). When this occurs, the hypolipidemic effects of NA cannot be explained by reduced FFA delivery to the liver.…”

mentioning

confidence: 99%

“…hypolipidemic drug; free fatty acids; perilipin; phosphodiesterase; triglyceride synthesis; insulin resistance; nicotinic acid receptor; microarray analysis NICOTINIC ACID (NA; or niacin) is a B-group vitamin. In addition to its function as a vitamin, NA, in high doses, has been used as a lipid drug for five decades (6, 21); it produces very desirable effects such as decreasing plasma triglycerides (TG), VLDL, and LDL-cholesterol levels and increasing HDL-cholesterol levels (14,38). Major clinical trials have demonstrated that NA treatment reduces the progression of atherosclerotic cardiovascular disease (9, 18).…”

mentioning

confidence: 99%

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Choi

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue. Am J Physiol Endocrinol Metab 300: E1012-E1021, 2011. First published March 8, 2011; doi:10.1152/ajpendo.00650.2010.-Nicotinic acid (NA) has been used as a lipid drug for five decades. The lipidlowering effects of NA are attributed to its ability to suppress lipolysis in adipocytes and lower plasma FFA levels. However, plasma FFA levels often rebound during NA treatment, offsetting some of the lipid-lowering effects of NA and/or causing insulin resistance, but the underlying mechanisms are unclear. The present study was designed to determine whether a prolonged, continuous NA infusion in rats produces a FFA rebound and/or insulin resistance. NA infusion rapidly lowered plasma FFA levels (Ͼ60%, P Ͻ 0.01), and this effect was maintained for Ն5 h. However, when this infusion was extended to 24 h, plasma FFA levels rebounded to the levels of saline-infused control rats. This was not due to a downregulation of NA action, because when the NA infusion was stopped, plasma FFA levels rapidly increased more than twofold (P Ͻ 0.01), indicating that basal lipolysis was increased. Microarray analysis revealed many changes in gene expression in adipose tissue, which would contribute to the increase in basal lipolysis. In particular, phosphodiesterase-3B gene expression decreased significantly, which would increase cAMP levels and thus lipolysis. Hyperinsulinemic glucose clamps showed that insulin's action on glucose metabolism was improved during 24-h NA infusion but became impaired with increased plasma FFA levels after cessation of NA infusion. In conclusion, a 24-h continuous NA infusion in rats resulted in an FFA rebound, which appeared to be due to altered gene expression and increased basal lipolysis in adipose tissue. In addition, our data support a previous suggestion that insulin resistance develops as a result of FFA rebound during NA treatment. Thus, the present study provides an animal model and potential molecular mechanisms of FFA rebound and insulin resistance, observed in clinical studies with chronic NA treatment. hypolipidemic drug; free fatty acids; perilipin; phosphodiesterase; triglyceride synthesis; insulin resistance; nicotinic acid receptor; microarray analysis NICOTINIC ACID (NA; or niacin) is a B-group vitamin. In addition to its function as a vitamin, NA, in high doses, has been used as a lipid drug for five decades (6, 21); it produces very desirable effects such as decreasing plasma triglycerides (TG), VLDL, and LDL-cholesterol levels and increasing HDL-cholesterol levels (14,38). Major clinical trials have demonstrated that NA treatment reduces the progression of atherosclerotic cardiovascular disease (9, 18). The lipid-lowering effects of NA have traditionally been attributed to its antilipolytic effect in adipocytes (10). NA binds to and stimulates a G proteincoupled receptor [i.e., GPR109A or HM74A (37, 41)] in the plasma membrane of adipo...

show abstract

“…In contrast to fibrates, nicotinic acid exerts a larger effect on HDL 2 than HDL 3 [57][58][59]. Conversely these agents are less potent than fibrates in reducing triglyceride levels with reductions generally around 20%.…”

Section: Nicotinic Acid Derivativesmentioning

confidence: 84%

Pharmacotherapy and HDL Cholesterol

Dart¹

2005

CMCIEMA

View full text Add to dashboard Cite

The concentration of HDL cholesterol is a powerful predictor of the occurrence of cardiovascular events, with a possible causal relationship between these variables. As such, the ability of pharmacological agents to influence HDL levels, and to affect the related processes such as reverse cholesterol transport, is of considerable relevance to the prevention and treatment of cardiovascular disease.Whilst currently available lipid modifying therapy does influence HDL cholesterol levels, and those of its sub-fractions, the effects are generally modest in comparison with the effects which can be achieved in reducing levels of LDL cholesterol. Thus, HMG CoA reductase inhibitors at the prevailing doses generally increase HDL cholesterol by no more than 10%. Fibrates induce a somewhat similar response. Somewhat larger effects are seen with niacin, and smaller effects with ezetemibe. CETP inhibition by agents such as torcetrapib are able to produce more marked effects. Knowledge of the effects of these agents on functional processes in man, such as reverse cholesterol transport is limited.Evidence that elevation of plasma HDL levels can causally influence cardiovascular outcomes is largely dependent on studies with agents which principally influence HDL and triglyceride levels, rather than LDL, and in subjects with low HDL cholesterol levels at baseline. Trial data does not suggest that HDL modification is a major contributor to the clear beneficial effects of HMG CoA reductase inhibitions. Outcome trials with agents, such as torcetrapib, which effect larger changes in HDL cholesterol should give clearer insight into the potential therapeutic benefits of such strategies. However, newer approaches will be required to evaluate the efficacy of agents designed to improve functional aspects of HDL cholesterol such as cellular cholesterol efflux, as distinct from functions directly dependent on HDL cholesterol levels.

show abstract

Effects of Nicotinic Acid and its Derivatives on Lipid Metabolism and Other Metabolic Factors Related to Atherosclerosis

Cited by 9 publications

References 19 publications

Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment

Widespread effects of nicotinic acid on gene expression in insulin-sensitive tissues: implications for unwanted effects of nicotinic acid treatment

Continuous 24-h nicotinic acid infusion in rats causes FFA rebound and insulin resistance by altering gene expression and basal lipolysis in adipose tissue

Pharmacotherapy and HDL Cholesterol

Contact Info

Product

Resources

About