The Experts below are selected from a list of 9825 Experts worldwide ranked by ideXlab platform
Moti L. Kashyap - One of the best experts on this subject based on the ideXlab platform.
-
Niacin inhibits fat accumulation oxidative stress and inflammatory cytokine il 8 in cultured hepatocytes impact on non alcoholic fatty liver disease
Metabolism-clinical and Experimental, 2015Co-Authors: Shobha H Ganji, Moti L. Kashyap, Vaijinath S. KamannaAbstract:Abstract Objective Non-alcoholic fatty liver disease (NAFLD) is a common disorder characterized by excessive hepatic fat accumulation, production of reactive oxygen species (ROS), inflammation and potentially resulting in non-alcoholic steatohepatitis (NASH), cirrhosis and end-stage liver disease. Recently, we have shown that Niacin significantly prevented hepatic steatosis and regressed pre-existing steatosis in high-fat fed rat model of NAFLD. To gain further insight into the cellular mechanisms, this study investigated the effect of Niacin on human hepatocyte fat accumulation, ROS production, and inflammatory mediator IL-8 secretion. Materials and methods Human hepatoblastoma cell line HepG2 or human primary hepatocytes were first stimulated with palmitic acid followed by treatment with Niacin or control for 24 h. Results The data indicated that Niacin (at 0.25 and 0.5 mmol/L doses) significantly inhibited palmitic acid-induced fat accumulation in human hepatocytes by 45–62%. This effect was associated with inhibition of diacylglycerol acyltransferase 2 (DGAT2) mRNA expression without affecting the mRNA expression of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1). Niacin attenuated hepatocyte ROS production and it also inhibited NADPH oxidase activity. Niacin reduced palmitic acid-induced IL-8 levels. Conclusions These findings suggest that Niacin, through inhibiting hepatocyte DGAT2 and NADPH oxidase activity, attenuates hepatic fat accumulation and ROS production respectively. Decreased ROS production, at least in part, may have contributed to the inhibition of pro-inflammatory IL-8 levels. These mechanistic studies may be useful for the clinical development of Niacin and Niacin-related compounds for the treatment of NAFLD/NASH and its complications.
-
the mechanism and mitigation of Niacin induced flushing
International Journal of Clinical Practice, 2009Co-Authors: Vaijinath S. Kamanna, Shobha H Ganji, Moti L. KashyapAbstract:SUMMARY Aims: To summarise the metabolic responses to Niacin that can lead to flushing and to critically evaluate flushing mitigation research. Methods and results: This comprehensive review of the mechanism of action of Niacin-induced flushing critically evaluates research regarding flushing mitigating formulations and agents. Niacin induces flushing through dermal Langerhans cells where the activation of G protein-coupled receptor 109A (GPR109A) increases arachidonic acid and prostaglandins, such as prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2), subsequently activating prostaglandin D2 receptor (DP1), prostaglandin E2 receptor (EP2) and prostaglandin E receptor 4 (EP4) in capillaries and causing cutaneous vasodilatation. Controlling Niacin absorption rates, inhibiting prostaglandin production, or blocking DP1 ,E P2 and EP4 receptors can inhibit flushing. Niacin extended-release (NER) formulations have reduced flushing incidence, duration and severity relative to crystalline immediate-release Niacin with similar lipid efficacy. Non-steroidal anti-inflammatory drugs (NSAIDs), notably aspirin given 30 min before NER at bedtime, further reduce flushing. An antagonist to the DP1 receptor (laropiprant) combined with an ER Niacin formulation can reduce flushing; however, significant residual flushing occurs with clinically-relevant dosages. Conclusions: Niacin is an attractive option for treating dyslipidemic patients, and tolerance to Niacin-induced flushing develops rapidly. Healthcare professionals should particularly address flushing during Niacin dose titration. Review Criteria Research regarding the mechanism of action of Niacin and the formulations and agents used in the mitigation of flushing were systematically reviewed and summarised. PubMed was searched from 1960 to 2008 using the terms Niacin, flushing, laropiprant, prostaglandins and aspirin. All hits were reviewed for inclusion of mechanism of action, and pertinent articles were included, excluding results which had been subsequently disproven.
-
Niacin inhibits vascular oxidative stress redox sensitive genes and monocyte adhesion to human aortic endothelial cells
Atherosclerosis, 2009Co-Authors: Moti L. Kashyap, Vaijinath S. Kamanna, Shobha H Ganji, Shucun Qin, Linhua ZhangAbstract:In pharmacological doses, nicotinic acid (Niacin) reduces myocardial infarction, stroke and atherosclerosis. The beneficial effects of Niacin on lipoproteins are thought to mediate these effects. We hypothesized that Niacin inhibits oxidative stress and redox-sensitive inflammatory genes that play a critical role in early atherogenesis. In cultured human aortic endothelial cells (HAEC), Niacin increased nicotinamide adenine dinucleotide phosphate (NAD(P)H) levels by 54% and reduced glutathione (GSH) by 98%. Niacin inhibited: (a) angiotensin II (ANG II)-induced reactive oxygen species (ROS) production by 24-86%, (b) low density lipoprotein (LDL) oxidation by 60%, (c) tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation by 46%, vascular cell adhesion molecule-1 (VCAM-1) by 77-93%, monocyte chemotactic protein-1 (MCP-1) secretion by 34-124%, and (d) in a functional assay TNF-alpha-induced monocyte adhesion to HAEC (41-54%). These findings indicate for the first time that Niacin inhibits vascular inflammation by decreasing endothelial ROS production and subsequent LDL oxidation and inflammatory cytokine production, key events involved in atherogenesis. Initial data presented herein support the novel concept that Niacin has vascular anti-inflammatory and potentially anti-atherosclerotic properties independent of its effects on lipid regulation.
-
mechanism of action of Niacin
American Journal of Cardiology, 2008Co-Authors: Vaijinath S. Kamanna, Moti L. KashyapAbstract:Nicotinic acid (Niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B–containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I–containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of Niacin and challenged older concepts. There are new data on (1) how Niacin affects triglycerides (TGs) and apo B–containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific Niacin receptor in adipocytes and immune cells, (5) how Niacin causes flushing, and (6) the characterization of a Niacin transport system in liver and intestinal cells. New findings indicate that Niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase–2, a key enzyme for TG synthesis. The inhibition of TG synthesis by Niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that Niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI–mediated cholesterol esters. Decreased HDL–apo A-I catabolism by Niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that Niacin, by inhibiting the hepatocyte surface expression of β-chain adenosine triphosphate synthase (a recently reported HDL–apo A-I holoparticle receptor), inhibits the removal of HDL–apo A-I. Recent studies indicate that Niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The Niacin flush results from the stimulation of prostaglandins D 2 and E 2 by subcutaneous Langerhans cells via the G protein–coupled receptor 109A Niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein–coupled receptor 109A Niacin receptor has been a widely suggested mechanism of Niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of Niacin.
-
nicotinic acid Niacin receptor agonists will they be useful therapeutic agents
American Journal of Cardiology, 2007Co-Authors: Vaijinath S. Kamanna, Moti L. KashyapAbstract:Nicotinic acid (Niacin) favorably affects very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and lipoprotein (a) (LP[a]) and increases high-density lipoprotein (HDL). Emerging data indicates vascular anti-inflammatory properties to additionally account for Niacin's proven effects in cardiovascular disease. Recent evidence indicates that Niacin acts on GPR109A and GPR109B (HM74A and HM74, respectively), receptors expressed in adipocytes and immune cells. In adipocytes, GPR109A activation reduces triglyceride (TG) lipolysis, resulting in decreased free fatty acid (FFA) mobilization to the liver. In humans, this mechanism has yet to be confirmed because the plasma FFA decrease is transient and is followed by a rebound increase in FFA levels. New evidence indicates Niacin directly inhibits diacylglycerol acyltransferase 2 (DGAT2) isolated from human hepatocytes, resulting in accelerated hepatic apolipoprotein (apo)B degradation and decreased apoB secretion, thus explaining reductions in VLDL and LDL. This raises important questions as to whether stimulation of GPR109A in adipocytes or inhibition of DGAT2 in liver by Niacin best explain the reduction in VLDL and LDL in dyslipidemic patients. Kinetic and in vitro studies indicate that Niacin retards the hepatic catabolism of apoA-I but not liver scavenger receptor B1-mediated cholesterol esters, suggesting that Niacin inhibits hepatic holoparticle HDL removal. Indeed, recent preliminary evidence suggests that Niacin decreases surface expression of hepatic β-chain of adenosine triphosphate synthase, which has been implicated in apoA-I/HDL holoparticle catabolism. GPR109A-mediated production of prostaglandin D 2 in macrophages and Langerhan cells causes skin capillary vasodilation and explains, in part, Niacin's effect on flushing. Development of Niacin receptor agonists would, theoretically, result in adipocyte TG accumulation (and clinical adiposity) and increased flushing. This raises questions about Niacin receptor agonists as therapeutic agents. Several Niacin receptor agonists have been developed and patented, but their clinical effects have not been described. Future research is needed to determine whether Niacin receptor agonists will demonstrate all the beneficial properties of nicotinic acid on atherosclerosis and without significant adverse effects.
Vaijinath S. Kamanna - One of the best experts on this subject based on the ideXlab platform.
-
Niacin inhibits fat accumulation oxidative stress and inflammatory cytokine il 8 in cultured hepatocytes impact on non alcoholic fatty liver disease
Metabolism-clinical and Experimental, 2015Co-Authors: Shobha H Ganji, Moti L. Kashyap, Vaijinath S. KamannaAbstract:Abstract Objective Non-alcoholic fatty liver disease (NAFLD) is a common disorder characterized by excessive hepatic fat accumulation, production of reactive oxygen species (ROS), inflammation and potentially resulting in non-alcoholic steatohepatitis (NASH), cirrhosis and end-stage liver disease. Recently, we have shown that Niacin significantly prevented hepatic steatosis and regressed pre-existing steatosis in high-fat fed rat model of NAFLD. To gain further insight into the cellular mechanisms, this study investigated the effect of Niacin on human hepatocyte fat accumulation, ROS production, and inflammatory mediator IL-8 secretion. Materials and methods Human hepatoblastoma cell line HepG2 or human primary hepatocytes were first stimulated with palmitic acid followed by treatment with Niacin or control for 24 h. Results The data indicated that Niacin (at 0.25 and 0.5 mmol/L doses) significantly inhibited palmitic acid-induced fat accumulation in human hepatocytes by 45–62%. This effect was associated with inhibition of diacylglycerol acyltransferase 2 (DGAT2) mRNA expression without affecting the mRNA expression of fatty acid synthase (FAS) and carnitine palmitoyltransferase 1 (CPT1). Niacin attenuated hepatocyte ROS production and it also inhibited NADPH oxidase activity. Niacin reduced palmitic acid-induced IL-8 levels. Conclusions These findings suggest that Niacin, through inhibiting hepatocyte DGAT2 and NADPH oxidase activity, attenuates hepatic fat accumulation and ROS production respectively. Decreased ROS production, at least in part, may have contributed to the inhibition of pro-inflammatory IL-8 levels. These mechanistic studies may be useful for the clinical development of Niacin and Niacin-related compounds for the treatment of NAFLD/NASH and its complications.
-
the mechanism and mitigation of Niacin induced flushing
International Journal of Clinical Practice, 2009Co-Authors: Vaijinath S. Kamanna, Shobha H Ganji, Moti L. KashyapAbstract:SUMMARY Aims: To summarise the metabolic responses to Niacin that can lead to flushing and to critically evaluate flushing mitigation research. Methods and results: This comprehensive review of the mechanism of action of Niacin-induced flushing critically evaluates research regarding flushing mitigating formulations and agents. Niacin induces flushing through dermal Langerhans cells where the activation of G protein-coupled receptor 109A (GPR109A) increases arachidonic acid and prostaglandins, such as prostaglandin D2 (PGD2) and prostaglandin E2 (PGE2), subsequently activating prostaglandin D2 receptor (DP1), prostaglandin E2 receptor (EP2) and prostaglandin E receptor 4 (EP4) in capillaries and causing cutaneous vasodilatation. Controlling Niacin absorption rates, inhibiting prostaglandin production, or blocking DP1 ,E P2 and EP4 receptors can inhibit flushing. Niacin extended-release (NER) formulations have reduced flushing incidence, duration and severity relative to crystalline immediate-release Niacin with similar lipid efficacy. Non-steroidal anti-inflammatory drugs (NSAIDs), notably aspirin given 30 min before NER at bedtime, further reduce flushing. An antagonist to the DP1 receptor (laropiprant) combined with an ER Niacin formulation can reduce flushing; however, significant residual flushing occurs with clinically-relevant dosages. Conclusions: Niacin is an attractive option for treating dyslipidemic patients, and tolerance to Niacin-induced flushing develops rapidly. Healthcare professionals should particularly address flushing during Niacin dose titration. Review Criteria Research regarding the mechanism of action of Niacin and the formulations and agents used in the mitigation of flushing were systematically reviewed and summarised. PubMed was searched from 1960 to 2008 using the terms Niacin, flushing, laropiprant, prostaglandins and aspirin. All hits were reviewed for inclusion of mechanism of action, and pertinent articles were included, excluding results which had been subsequently disproven.
-
Niacin inhibits vascular oxidative stress redox sensitive genes and monocyte adhesion to human aortic endothelial cells
Atherosclerosis, 2009Co-Authors: Moti L. Kashyap, Vaijinath S. Kamanna, Shobha H Ganji, Shucun Qin, Linhua ZhangAbstract:In pharmacological doses, nicotinic acid (Niacin) reduces myocardial infarction, stroke and atherosclerosis. The beneficial effects of Niacin on lipoproteins are thought to mediate these effects. We hypothesized that Niacin inhibits oxidative stress and redox-sensitive inflammatory genes that play a critical role in early atherogenesis. In cultured human aortic endothelial cells (HAEC), Niacin increased nicotinamide adenine dinucleotide phosphate (NAD(P)H) levels by 54% and reduced glutathione (GSH) by 98%. Niacin inhibited: (a) angiotensin II (ANG II)-induced reactive oxygen species (ROS) production by 24-86%, (b) low density lipoprotein (LDL) oxidation by 60%, (c) tumor necrosis factor alpha (TNF-alpha)-induced NF-kappaB activation by 46%, vascular cell adhesion molecule-1 (VCAM-1) by 77-93%, monocyte chemotactic protein-1 (MCP-1) secretion by 34-124%, and (d) in a functional assay TNF-alpha-induced monocyte adhesion to HAEC (41-54%). These findings indicate for the first time that Niacin inhibits vascular inflammation by decreasing endothelial ROS production and subsequent LDL oxidation and inflammatory cytokine production, key events involved in atherogenesis. Initial data presented herein support the novel concept that Niacin has vascular anti-inflammatory and potentially anti-atherosclerotic properties independent of its effects on lipid regulation.
-
mechanism of action of Niacin
American Journal of Cardiology, 2008Co-Authors: Vaijinath S. Kamanna, Moti L. KashyapAbstract:Nicotinic acid (Niacin) has long been used for the treatment of lipid disorders and cardiovascular disease. Niacin favorably affects apolipoprotein (apo) B–containing lipoproteins (eg, very-low-density lipoprotein [VLDL], low-density lipoprotein [LDL], lipoprotein[a]) and increases apo A-I–containing lipoproteins (high-density lipoprotein [HDL]). Recently, new discoveries have enlarged our understanding of the mechanism of action of Niacin and challenged older concepts. There are new data on (1) how Niacin affects triglycerides (TGs) and apo B–containing lipoprotein metabolism in the liver, (2) how it affects apo A-I and HDL metabolism, (3) how it affects vascular anti-inflammatory events, (4) a specific Niacin receptor in adipocytes and immune cells, (5) how Niacin causes flushing, and (6) the characterization of a Niacin transport system in liver and intestinal cells. New findings indicate that Niacin directly and noncompetitively inhibits hepatocyte diacylglycerol acyltransferase–2, a key enzyme for TG synthesis. The inhibition of TG synthesis by Niacin results in accelerated intracellular hepatic apo B degradation and the decreased secretion of VLDL and LDL particles. Previous kinetic studies in humans and recent in vitro cell culture findings indicate that Niacin retards mainly the hepatic catabolism of apo A-I (vs apo A-II) but not scavenger receptor BI–mediated cholesterol esters. Decreased HDL–apo A-I catabolism by Niacin explains the increases in HDL half-life and concentrations of lipoprotein A-I HDL subfractions, which augment reverse cholesterol transport. Initial data suggest that Niacin, by inhibiting the hepatocyte surface expression of β-chain adenosine triphosphate synthase (a recently reported HDL–apo A-I holoparticle receptor), inhibits the removal of HDL–apo A-I. Recent studies indicate that Niacin increases vascular endothelial cell redox state, resulting in the inhibition of oxidative stress and vascular inflammatory genes, key cytokines involved in atherosclerosis. The Niacin flush results from the stimulation of prostaglandins D 2 and E 2 by subcutaneous Langerhans cells via the G protein–coupled receptor 109A Niacin receptor. Although decreased free fatty acid mobilization from adipose tissue via the G protein–coupled receptor 109A Niacin receptor has been a widely suggested mechanism of Niacin to decrease TGs, physiologically and clinically, this pathway may be only a minor factor in explaining the lipid effects of Niacin.
-
nicotinic acid Niacin receptor agonists will they be useful therapeutic agents
American Journal of Cardiology, 2007Co-Authors: Vaijinath S. Kamanna, Moti L. KashyapAbstract:Nicotinic acid (Niacin) favorably affects very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and lipoprotein (a) (LP[a]) and increases high-density lipoprotein (HDL). Emerging data indicates vascular anti-inflammatory properties to additionally account for Niacin's proven effects in cardiovascular disease. Recent evidence indicates that Niacin acts on GPR109A and GPR109B (HM74A and HM74, respectively), receptors expressed in adipocytes and immune cells. In adipocytes, GPR109A activation reduces triglyceride (TG) lipolysis, resulting in decreased free fatty acid (FFA) mobilization to the liver. In humans, this mechanism has yet to be confirmed because the plasma FFA decrease is transient and is followed by a rebound increase in FFA levels. New evidence indicates Niacin directly inhibits diacylglycerol acyltransferase 2 (DGAT2) isolated from human hepatocytes, resulting in accelerated hepatic apolipoprotein (apo)B degradation and decreased apoB secretion, thus explaining reductions in VLDL and LDL. This raises important questions as to whether stimulation of GPR109A in adipocytes or inhibition of DGAT2 in liver by Niacin best explain the reduction in VLDL and LDL in dyslipidemic patients. Kinetic and in vitro studies indicate that Niacin retards the hepatic catabolism of apoA-I but not liver scavenger receptor B1-mediated cholesterol esters, suggesting that Niacin inhibits hepatic holoparticle HDL removal. Indeed, recent preliminary evidence suggests that Niacin decreases surface expression of hepatic β-chain of adenosine triphosphate synthase, which has been implicated in apoA-I/HDL holoparticle catabolism. GPR109A-mediated production of prostaglandin D 2 in macrophages and Langerhan cells causes skin capillary vasodilation and explains, in part, Niacin's effect on flushing. Development of Niacin receptor agonists would, theoretically, result in adipocyte TG accumulation (and clinical adiposity) and increased flushing. This raises questions about Niacin receptor agonists as therapeutic agents. Several Niacin receptor agonists have been developed and patented, but their clinical effects have not been described. Future research is needed to determine whether Niacin receptor agonists will demonstrate all the beneficial properties of nicotinic acid on atherosclerosis and without significant adverse effects.
R Lorenz - One of the best experts on this subject based on the ideXlab platform.
-
stimulation of cd36 and the key effector of reverse cholesterol transport atp binding cassette a1 in monocytoid cells by Niacin
Biochemical Pharmacology, 2004Co-Authors: Tina Rubic, Matthias Trottmann, R LorenzAbstract:Niacin, the first lipid lowering drug shown to improve survival after myocardial infarction, decreases LDL and increases HDL cholesterol levels. These effects cannot fully be explained by its suspected mechanism of action, inhibition of lipolysis and hepatic VLDL synthesis. Niacin has also been shown to interfere with the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and massively stimulate prostaglandin D2 (PGD2) formation. The major metabolite of PGD2, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), was recently identified as the most potent endogenous PPARγ activator. We, therefore, studied the effects of Niacin on the PPARγ- and cAMP-dependent expression of receptors promoting reverse cholesterol transport. The transcription of PPARγ-, HDL-, LDL- and scavenger-receptors and the sterol exporter ABCA1, were measured by quantitative RT-PCR and cellular cholesterol efflux and PPARγ activation studied in macrophage and hepatocyte models. Niacin stimulated the translocation of PPARγ and the transcription of PPARγ, CD36 and ABCA1 in monocytoid cells, whereas the LDL-receptor (LDL-R) was unchanged. Thereby Niacin enhanced HDL-mediated cholesterol efflux from the cells resulting in a reduced cellular cholesterol content. The Niacin effect on CD36 but not on ABCA1 was prevented by cyclooxygenase inhibition, whereas the Niacin effect on ABCA1 but not on CD36 was prevented by PKA inhibition, suggesting mediation by the 15d-PGJ2/PPARγ and the cAMP/PKA pathways, respectively. These new actions of Niacin on several key effectors of reverse cholesterol transport out of the vessel wall provide a rational to expect regression of atherosclerosis and test the combination of Niacin with statins for an overadditive clinical benefit.
-
stimulation of cd36 and the key effector of reverse cholesterol transport atp binding cassette a1 in monocytoid cells by Niacin
Biochemical Pharmacology, 2004Co-Authors: Tina Rubic, Matthias Trottmann, R LorenzAbstract:Niacin, the first lipid lowering drug shown to improve survival after myocardial infarction, decreases LDL and increases HDL cholesterol levels. These effects cannot fully be explained by its suspected mechanism of action, inhibition of lipolysis and hepatic VLDL synthesis. Niacin has also been shown to interfere with the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and massively stimulate prostaglandin D2 (PGD2) formation. The major metabolite of PGD2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), was recently identified as the most potent endogenous PPARgamma activator. We, therefore, studied the effects of Niacin on the PPARgamma- and cAMP-dependent expression of receptors promoting reverse cholesterol transport. The transcription of PPARgamma-, HDL-, LDL- and scavenger-receptors and the sterol exporter ABCA1, were measured by quantitative RT-PCR and cellular cholesterol efflux and PPARgamma activation studied in macrophage and hepatocyte models. Niacin stimulated the translocation of PPARgamma and the transcription of PPARgamma, CD36 and ABCA1 in monocytoid cells, whereas the LDL-receptor (LDL-R) was unchanged. Thereby Niacin enhanced HDL-mediated cholesterol efflux from the cells resulting in a reduced cellular cholesterol content. The Niacin effect on CD36 but not on ABCA1 was prevented by cyclooxygenase inhibition, whereas the Niacin effect on ABCA1 but not on CD36 was prevented by PKA inhibition, suggesting mediation by the 15d-PGJ2/PPARgamma and the cAMP/PKA pathways, respectively. These new actions of Niacin on several key effectors of reverse cholesterol transport out of the vessel wall provide a rational to expect regression of atherosclerosis and test the combination of Niacin with statins for an overadditive clinical benefit.
Keith Gottesdiener - One of the best experts on this subject based on the ideXlab platform.
-
suppression of Niacin induced vasodilation with an antagonist to prostaglandin d2 receptor subtype 1
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Inge De Lepeleire, L A Wenning, T M Crumley, Gary P Oneill, Nicole Michiels, E Vets, John A Wagner, Keith GottesdienerAbstract:Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with Niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D2 receptor subtype 1 (DP1), which may mediate Niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on Niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) Niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER Niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of Niacin-induced vasodilation. Clinical Pharmacology & Therapeutics (2007) 81, 849–857. doi:10.1038/sj.clpt.6100180; published online 28 March 2007
-
suppression of Niacin induced vasodilation with an antagonist to prostaglandin d2 receptor subtype 1
Clinical Pharmacology & Therapeutics, 2007Co-Authors: Eseng Lai, L A Wenning, T M Crumley, Gary P Oneill, Inge De Lepeleire, Nicole Michiels, E Vets, John A Wagner, Fang Liu, Keith GottesdienerAbstract:Niacin (nicotinic acid) reduces cardiovascular events in patients with dyslipidemia. However, symptoms associated with Niacin-induced vasodilation (e.g., flushing) have limited its use. Laropiprant is a selective antagonist of the prostaglandin D(2) receptor subtype 1 (DP1), which may mediate Niacin-induced vasodilation. The aim of this proof-of-concept study was to evaluate the effects of laropiprant (vs placebo) on Niacin-induced cutaneous vasodilation. Coadministration of laropiprant 30, 100, and 300 mg with extended-release (ER) Niacin significantly lowered flushing symptom scores (by approximately 50% or more) and also significantly reduced malar skin blood flow measured by laser Doppler perfusion imaging. Laropiprant was effective after multiple doses in reducing symptoms of flushing and attenuating the increased malar skin blood flow induced by ER Niacin. In conclusion, the DP1 receptor antagonist laropiprant was effective in suppressing both subjective and objective manifestations of Niacin-induced vasodilation.
Tina Rubic - One of the best experts on this subject based on the ideXlab platform.
-
stimulation of cd36 and the key effector of reverse cholesterol transport atp binding cassette a1 in monocytoid cells by Niacin
Biochemical Pharmacology, 2004Co-Authors: Tina Rubic, Matthias Trottmann, R LorenzAbstract:Niacin, the first lipid lowering drug shown to improve survival after myocardial infarction, decreases LDL and increases HDL cholesterol levels. These effects cannot fully be explained by its suspected mechanism of action, inhibition of lipolysis and hepatic VLDL synthesis. Niacin has also been shown to interfere with the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and massively stimulate prostaglandin D2 (PGD2) formation. The major metabolite of PGD2, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), was recently identified as the most potent endogenous PPARγ activator. We, therefore, studied the effects of Niacin on the PPARγ- and cAMP-dependent expression of receptors promoting reverse cholesterol transport. The transcription of PPARγ-, HDL-, LDL- and scavenger-receptors and the sterol exporter ABCA1, were measured by quantitative RT-PCR and cellular cholesterol efflux and PPARγ activation studied in macrophage and hepatocyte models. Niacin stimulated the translocation of PPARγ and the transcription of PPARγ, CD36 and ABCA1 in monocytoid cells, whereas the LDL-receptor (LDL-R) was unchanged. Thereby Niacin enhanced HDL-mediated cholesterol efflux from the cells resulting in a reduced cellular cholesterol content. The Niacin effect on CD36 but not on ABCA1 was prevented by cyclooxygenase inhibition, whereas the Niacin effect on ABCA1 but not on CD36 was prevented by PKA inhibition, suggesting mediation by the 15d-PGJ2/PPARγ and the cAMP/PKA pathways, respectively. These new actions of Niacin on several key effectors of reverse cholesterol transport out of the vessel wall provide a rational to expect regression of atherosclerosis and test the combination of Niacin with statins for an overadditive clinical benefit.
-
stimulation of cd36 and the key effector of reverse cholesterol transport atp binding cassette a1 in monocytoid cells by Niacin
Biochemical Pharmacology, 2004Co-Authors: Tina Rubic, Matthias Trottmann, R LorenzAbstract:Niacin, the first lipid lowering drug shown to improve survival after myocardial infarction, decreases LDL and increases HDL cholesterol levels. These effects cannot fully be explained by its suspected mechanism of action, inhibition of lipolysis and hepatic VLDL synthesis. Niacin has also been shown to interfere with the cyclic AMP (cAMP)/protein kinase A (PKA) pathway and massively stimulate prostaglandin D2 (PGD2) formation. The major metabolite of PGD2, 15-deoxy-Delta(12,14)-prostaglandin J2 (15d-PGJ2), was recently identified as the most potent endogenous PPARgamma activator. We, therefore, studied the effects of Niacin on the PPARgamma- and cAMP-dependent expression of receptors promoting reverse cholesterol transport. The transcription of PPARgamma-, HDL-, LDL- and scavenger-receptors and the sterol exporter ABCA1, were measured by quantitative RT-PCR and cellular cholesterol efflux and PPARgamma activation studied in macrophage and hepatocyte models. Niacin stimulated the translocation of PPARgamma and the transcription of PPARgamma, CD36 and ABCA1 in monocytoid cells, whereas the LDL-receptor (LDL-R) was unchanged. Thereby Niacin enhanced HDL-mediated cholesterol efflux from the cells resulting in a reduced cellular cholesterol content. The Niacin effect on CD36 but not on ABCA1 was prevented by cyclooxygenase inhibition, whereas the Niacin effect on ABCA1 but not on CD36 was prevented by PKA inhibition, suggesting mediation by the 15d-PGJ2/PPARgamma and the cAMP/PKA pathways, respectively. These new actions of Niacin on several key effectors of reverse cholesterol transport out of the vessel wall provide a rational to expect regression of atherosclerosis and test the combination of Niacin with statins for an overadditive clinical benefit.