The Effect of Nicotinic Acid on the Plasma Free Fatty Acids Demonstration of a Metabolic Type of Sympathicolysis

Carlson, Lars A.; Orö, Lars

doi:10.1111/j.0954-6820.1962.tb07203.x

Cited by 395 publications

(60 citation statements)

References 17 publications

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“…It was believed that niacin acts as an inhibitor of FFA mobilization from adipocytes (17)(18)(19). Carlson and Oro ( 17 ) found that niacin lowered the arterial plasma concentration of FFAs in fasting humans within minutes.…”

Section: Effect On Ldl and Vldlmentioning

confidence: 99%

“…The recent Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trial (see below) also found that in the niacin/ LRPT group, diabetic complications (typically hyperglycemia) were about twice as common as in the control group as a reason for dropping out of the trial (0.9% vs. 0.4%) ( 12 ). A proposed mechanism is the rebound increase in FFA levels following the transient FFA suppression induced by niacin ( 92 ), although this has been disputed ( 17 ).…”

Section: Diabetesmentioning

confidence: 99%

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Niacin, an old drug with a new twist

Song

FitzGerald

2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org the only approved drug with such an effect ( 1 ). It has proven to be an attractive option for those intolerant of statin treatment. It has been demonstrated to reduce risk of atherosclerotic cardiovascular disease ( 4 ). The clinical use of niacin has been markedly limited by cutaneous fl ushing. The molecular target of niacin responsible for lipid metabolic changes and fl ushing was unknown until 2003 ( 5-7 ), when the niacin receptor, namely HM74A in humans and PUMA-G in mice, was discovered. The niacin receptor, also known as GPR109A, was shown to be activated by niacin and to mediate its antilipolytic effect as well as the fl ushing effect ( 8-10 ). Interest in niacin has risen because there is still signifi cant residual risk in patients with intensive statin therapy ( 11 ). However, recent outcome trials ( 11, 12 ) failed to show niacin's benefi t on top of statin therapy in lipid-targeted approaches to reduce major cardiovascular events in high-risk patients. In this review we will summarize the pharmacology of niacin, with a particular emphasis on recent outcome trials, including discussion of their limitations . NIACIN'S LIPID EFFECTSNiacin has long been shown to have effects on lipids ( 13 ). Niacin increases high density lipoprotein cholesterol (HDLc), but reduces low density lipoprotein cholesterol (LDLc), VLDL cholesterol, and triglycerides (TGs) ( 14 ) Niacin is also known as vitamin B3. Chronic dietary defi ciency of niacin can cause pellagra ( 1 ). It is a precursor to NAD+/NADH and NADP+/NADPH, both of which play essential metabolic roles in living cells ( 2 ). Niacin has been used for more than half a century in the treatment of dyslipidemia. When Altschul, Hoffer, and Stephen ( 3 ) discovered that niacin could lower plasma levels of cholesterol, it was

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Section: Effect On Ldl and Vldlmentioning

confidence: 99%

Section: Diabetesmentioning

confidence: 99%

Niacin, an old drug with a new twist

Song

FitzGerald

2013

Journal of Lipid Research

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“…This effect was initially thought to be attributable to its antilipolytic effect in adipose tissue, thereby reducing FFA release from adipocytes and decreasing FFA fl ux to the liver ( 5, 6 ). However, although niacin initially reduces plasma FFA concentrations, this reduction is actually followed by a rebound within 1 to 9 h postdose, depending on the formulation used, and long-term treatment with niacin is associated with increases in plasma FFA, glucose, and insulin resistance ( 7,8 ). These observations suggest that the reduction of the FFA delivery to the liver may not be the main mechanism explaining the consistent and maintained plasma TG-lowering effect of niacin.…”

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confidence: 99%

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Chu

Yamashita

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org Nonalcoholic fatty liver disease (NAFLD) characterized by excessive accumulation of intrahepatic triglycerides is associated with multiple metabolic abnormalities that are important cardiovascular risk factors, including increased plasma triglycerides (TG), obesity, insulin resistance, diabetes, and the metabolic syndrome ( 1, 2 ). Hepatic steatosis, the earliest stage of the disease, arises from an imbalance between hepatic TG acquisition and removal ( 3 ). Increased supply to the liver of free fatty acids (FFA), the substrates for hepatic TG synthesis, from diet and adipose tissue and through increased de novo lipogenesis, promotes hepatic steatosis ( 3, 4 ).Nicotinic acid or niacin, one of the naturally occurring B vitamins (vitamin B3), effectively reduces plasma TG levels. This effect was initially thought to be attributable to its antilipolytic effect in adipose tissue, thereby reducing FFA release from adipocytes and decreasing FFA fl ux to the liver ( 5, 6 ). However, although niacin initially reduces plasma FFA concentrations, this reduction is actually followed by a rebound within 1 to 9 h postdose, depending on the formulation used, and long-term treatment with niacin is associated with increases in plasma FFA, glucose, and insulin resistance ( 7,8 ). These observations suggest that the reduction of the FFA delivery to the liver may not be the main mechanism explaining the consistent and maintained plasma TG-lowering effect of niacin.Recent in vitro and animal studies suggested that the TG-lowering effect of niacin might be mediated by its direct and noncompetitive inhibitory effect on hepatic diacylglycerol acyltransferase-2 (DGAT2), a key enzyme that catalyzes the fi nal step of TG synthesis ( 9, 10 ). Inhibition of mouse Dgat2 with antisense oligonucleotides in mice with obesity induced by high-fat diet or leptin-defi ciency Abstract Niacin reduces plasma triglycerides, but it may increase free fatty acids and insulin resistance during longterm treatment. We examined the effect of extended-release niacin on liver fat content in Chinese patients with dyslipidemia and whether the common diacylglycerol acyltransferase-2 ( DGAT2 ) polymorphisms infl uenced this effect. The 39 patients (baseline liver fat content: 12.8 ± 7.6%, triglycerides: 3.30 ± 1.67 mmol/l) were treated with niacin, gradually increasing the dose to 2 g/day for a total of 23 weeks. The liver fat content and visceral/subcutaneous fat was measured before and after treatment. Subjects were genotyped for the DGAT2 rs3060 and rs101899116 polymorphisms. There were signifi cant ( P < 0.001) reductions in plasma triglycerides ( ؊ 34.9 ± 37.6%), liver fat content ( ؊ 47.2 ± 32.8%), and visceral fat ( ؊ 6.3 ± 15.8%, P < 0.05) after niacin treatment. Mean body weight decreased by 1.46 ± 2.7% (1.17 ± 2.44 kg, P < 0.001) during the study, but liver fat changes remained signifi cant after adjustment for age, gender, and body weight changes [mean absolute change (95% CI): ؊ 6.1% ( ؊ 8.0, ؊ 4.3)...

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“…This increase subsides with long use of niacin (117). It was suggested that this effect could be related to the rebound increase in NEFA levels following the transient NEFA suppression induced by niacin (118), but this mechanism is questionable in long-term use of niacin (119). It was recently found in a mouse model that long-term niacin treatment resulted in insulin resistance that may be in part explained by a niacininduced downregulation of the cAMP-degrading enzyme phosphodiesterase 3B (120) or modulated through activation of the islet beta-cell HCA2, which induce PPARg -uncoupling protein 2 pathway (121).…”

Section: Effect On Glucose Homeostasis and Uric Acidmentioning

confidence: 99%

Pleiotropic effects of niacin: Current possibilities for its clinical use

et al. 2016

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Niacin was the first hypolipidemic drug to significantly reduce both major cardiovascular events and mortality in patients with cardiovascular disease. Niacin favorably influences all lipoprotein classes, including lipoprotein [a],and belongs to the most potent hypolipidemic drugs for increasing HDL-C. Moreover, niacin causes favorable changes to the qualitative composition of lipoprotein HDL. In addition to its pronounced hypolipidemic action, niacin exerts many other, non-hypolipidemic effects (e.g., antioxidative, anti-inflammatory, antithrombotic), which favorably influence the development and progression of atherosclerosis. These effects are dependent on activation of the specific receptor HCA2. Recent results published by the two large clinical studies, AIM-HIGH and HPS2-THRIVE, have led to the impugnation of niacin's role in future clinical practice. However, due to several methodological flaws in the AIM-HIGH and HPS2-THRIVE studies, the pleiotropic effects of niacin now deserve thorough evaluation. This review summarizes the present and possible future use of niacin in clinical practice in light of its newly recognized pleiotropic effects.

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The Effect of Nicotinic Acid on the Plasma Free Fatty Acids Demonstration of a Metabolic Type of Sympathicolysis

Cited by 395 publications

References 17 publications

Niacin, an old drug with a new twist

Niacin, an old drug with a new twist

Liver fat reduction with niacin is influenced by DGAT-2 polymorphisms in hypertriglyceridemic patients

Pleiotropic effects of niacin: Current possibilities for its clinical use

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