Reduction of Serum Cholesterol Levels and Beta-Lipoprotein Cholesterol Levels by Nicotinic Acid

Parsons, William Barclay; Flinn, John H.

doi:10.1001/archinte.1959.00270050105016

Cited by 88 publications

(18 citation statements)

References 11 publications

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“…On the other hand, there are some patients in whom the total sterol level drops significantly, and the mean drop is in the neighborhood of 15 per cent. This degree of response compares unfavorably with the therapeutic responses that have been obtained using dietary treatment with unsaturated fat, or low fat diets, or with nicotinic acid (30)(31)(32).…”

Section: Discussionmentioning

confidence: 85%

Effects of Triparanol (Mer-29) on Cholesterol Biosynthesis and on Blood Sterol Levels in Man*

Steinberg¹,

Avigan²,

Feigelson³

1961

J. Clin. Invest.

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Section: Discussionmentioning

confidence: 85%

Effects of Triparanol (Mer-29) on Cholesterol Biosynthesis and on Blood Sterol Levels in Man*

Steinberg¹,

Avigan²,

Feigelson³

1961

J. Clin. Invest.

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“…Perhaps the strongest evidence for a role of stratum corneum lipids in the modulation of stratum corneum desquamation derives from the observation that a number of scaling disorders occur in acquired or inherited defects of lipid metabolism. Ichthyosis, palmarplantar keratoderma, and acanthosis nigricans, occur as side effects of several drugs (26)(27)(28)(29) that interfere with cholesterol biosynthesis or lower serum cholesterol by as yet unknown mechanisms. As reported here, RXLI scales contain not only increased cholesterol sulfate, but also decreased free sterols, raising the possibility that the reduction of free sterols may also regulate desquamation in RXLI.…”

Section: Resultsmentioning

confidence: 99%

Stratum corneum lipids in disorders of cornification: increased cholesterol sulfate content of stratum corneum in recessive x-linked ichthyosis.

Williams¹,

Elias²

1981

J. Clin. Invest.

186

103

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A B S T R A C T Activity of the microsomal enzyme, steroid sulfatase, is absent in keratinocytes, fibroblasts, and leukocytes of patienits with recessive xlinked ichthyosis. This study was uiidertaken to determine if cholesterol sulfate, a substrate of this enzyme, accumulates in the pathological scale of these patients.Scales from 8 patients with recessive x-linked ichthyosis, 10 patienits with other fornms of ichthyosis, and normal human outer stratum corneum were extracted with chloroform/water (1:2:0.8 by vol) and lipids were fractionated by quantitative, sequential thin-layer chromatography. Cholesterol sulfate was identified by cochromatography in several solvent systemns, by its staining characteristics, by biochemical analysis, and by mass spectrometry. The mean cholesterol sulfate content of recessive x-linked ichthyotic scale was 12.5+0.8% of the total lipid, a fivefold increase over normal (P < 0.0025), whereas the cholesterol sulfate content of other ichthyotic scale was normal. This increase in cholesterol sulfate content was accompanied by a decrease in total neutral lipids (P < 0.0025) and free sterols (P < 0.025) but no change in sterol esters or total sterols. These results demonstrate that deficiency of steroid sulfatase in recessive x-linked ichthyosis results in excessive accumulation of a substrate, cholesterol sulfate, in the pathologic scale, which may underly the pathogenesis of the scaling in this disorder. Measurement of cholesterol sulfate content in scale provides an alternative method to enzymatic assay for the diagnosis of this form of ichthyosis.

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“…Since Altschul et al discovered nicotinic acid (niacin) lowered plasma cholesterol (Altschul et al 1955;Parsons Jr and Flinn 1959), it has been used as a broad-spectrum antiatherosclerosis agent for over 50 years because of its beneficial effects on lipid profiles in human (Carlson 2005), lowering levels of very-low-density lipoprotein (LDL), LDL, and triglycerides, while raising levels of high-density lipoprotein cholesterol (Benyo et al 2005;Hanson et al 2010;Eaton et al 1969;Ganji et al 2004;Le Goff et al 2004). However, its clinical use to patient is limited by the severe side effects of cutaneous vasodilation called flushing (Benyo et al 2005;Hanson et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor

et al. 2015

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Even though nicotinic acid (niacin) appears to have beneficial effects on human lipid profiles, niacin-induced cutaneous vasodilatation called flushing limits its remedy to patient. GPR109A is activated by niacin and mediates the anti-lipolytic effects. Based on the hypothesis that β-arrestin signaling mediates niacin-induced flushing, but not its anti-lipolytic effect, we tried to find GPR109A agonists which selectively elicit Gi-protein-biased signaling devoid of β-arrestin internalization using a β-lactamase assay. We identified a 4-(phenyl)thio-1H-pyrazole as a novel scaffold for GPR109A agonist in a high throughput screen, which has no carboxylic acid moiety known to be important for binding. While 1-nicotinoyl derivatives (5a-g, 6a-e) induced β-arrestin recruitment, 1-(pyrazin-2-oyl) derivatives were found to play as G-protein-biased agonists without GPR109A receptor internalization. The activity of compound 5a (EC50 = 45 nM) was similar to niacin (EC50 = 52 nM) and MK-6892 (EC50 = 74 nM) on calcium mobilization assay, but its activity at 10 μM on β-arrestin recruitment were around two and five times weaker than niacin and MK-6892, respectively. The development of G-protein biased GPR109A ligands over β-arrestin pathway is attainable and might be important in differentiation of pharmacological efficacy.

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Reduction of Serum Cholesterol Levels and Beta-Lipoprotein Cholesterol Levels by Nicotinic Acid

Cited by 88 publications

References 11 publications

Effects of Triparanol (Mer-29) on Cholesterol Biosynthesis and on Blood Sterol Levels in Man*

Effects of Triparanol (Mer-29) on Cholesterol Biosynthesis and on Blood Sterol Levels in Man*

Stratum corneum lipids in disorders of cornification: increased cholesterol sulfate content of stratum corneum in recessive x-linked ichthyosis.

Discovery of 4-(phenyl)thio-1H-pyrazole derivatives as agonists of GPR109A, a high affinity niacin receptor

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