Niacin: an old lipid drug in a new NAD+ dress

Romani, Mario; Hofer, Dina; Katsyuba, Elena; Auwerx, Johan

doi:10.1194/jlr.s092007

Cited by 51 publications

(40 citation statements)

References 66 publications

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“…As an energy substrate and cofactor for many enzymes, NAD + is critical for mitochondrial health and neuronal stress resistance [30,31]. NAD + is a crucial cofactor for cellular processes, such as glycolysis, fatty acid β-oxidation, tricarboxylic acid cycle, and DNA repair [32,33]. NAD + -dependent signaling, which is associated with neuronal development, survival, and function in the central nervous system, is implicated in neuroprotection [34].…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

Kim

Cho

2020

Mol Brain

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Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by memory loss and the presence of amyloid plaques and neurofibrillary tangles in the patients' brains. In this study, we investigated the alterations in metabolite profiles of the hippocampal tissues from 6, 8, and 12 month-old wild-type (WT) and 5xfamiliar AD (5xFAD) mice, an AD mouse model harboring 5 early-onset familiar AD mutations, which shows memory loss from approximately 5 months of age, by exploiting the untargeted metabolomics profiling. We found that nicotinamide and adenosine monophosphate levels have been significantly decreased while lysophosphatidylcholine (LysoPC) (16:0), LysoPC (18:0), and lysophosphatidylethanolamine (LysoPE) (16:0) levels have been significantly increased in the hippocampi from 5xFAD mice at 8 months or 12 months of age, compared to those from age-matched wild-type mice. In the present study, we focused on the role of nicotinamide and examined if replenishment of nicotinamide exerts attenuating effects on the reduction in dendritic spine density in hippocampal primary neurons from 5xFAD mice. Treatment with nicotinamide attenuated the deficits in spine density in the hippocampal primary neurons derived from 5xFAD mice, indicating a potential role of nicotinamide in the pathogenesis of AD. Taken together, these findings suggest that the decreased hippocampal nicotinamide level could be linked with AD pathogenesis and be a useful therapeutic target for AD.

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Section: Discussionmentioning

confidence: 99%

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

Kim

Cho

2020

Mol Brain

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“…Glycogen phosphorylase activity is negatively regulated by acetylation and SIRT1 increases glycogen phosphorylase activity [37]. Niacin is a substrate for NAD + synthesis and NAD + dependent activation of the deacetylase SIRT1 has been proposed to mediate some of niacin's effects [38][39][40]. However, repeated overnight injections of niacin but not nicotinamide, another NAD + precursor, decreased liver glycogen concentrations in rats [35,39].…”

Section: Discussionmentioning

confidence: 99%

“…We observed that niacin upregulated fed state hepatic CPT1 and PEPCK mRNA expression in GPR109a -/-mice ( Figures 3C and 3E). One possible GPR109a independent mechanism of niacin regulated gene expression is through NAD + mediated activation of SIRT1 [40]. SIRT1 activates the transcriptional coactivator peroxisome proliferator-activated receptor γ-coactivator 1α (PGC-1α) and PGC-1α upregulates hepatic expression of PEPCK and CPT1 [52][53][54].…”

Section: Discussionmentioning

confidence: 99%

The Role of GPR109a Signaling in Niacin Induced Effects on Fed and Fasted Hepatic Metabolism

Geisler¹,

Renquist²

2020

Preprint

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Signaling through GPR109a, the putative receptor for the endogenous ligand β-OH butyrate, inhibits adipose tissue lipolysis. Niacin, an anti-atherosclerotic drug that can induce insulin resistance, activates GPR109a at nM concentrations. GPR109a is not essential for niacin to improve serum lipid profiles. To better understand the involvement of GPR109a signaling in regulating glucose and lipid metabolism, we treated GPR109a wildtype (+/+) and knockout (-/-) mice with repeated overnight injections of saline or niacin in physiological states characterized by low (ad libitum fed) or high (16h fasted) concentrations of the endogenous ligand, β-OH butyrate. In the fed state, niacin increased expression of PEPCK mRNA independent of genotype, while increasing CPT1 mRNA only in GPR109a -/- mice. Niacin decreased fasting serum non-esterified fatty acid concentrations in both GPR109a +/+ and -/- mice. Independent of GPR109a expression, niacin blunted fast-induced hepatic triglyceride accumulation and peroxisome proliferator activated receptor α (PPARα) mRNA expression. Surprisingly, GPR109a knockout did not affect glucose or lipid homeostasis or hepatic gene expression in either fed or fasted mice. In turn, GPR109a does not appear to be essential for the metabolic response to the ketogenic state or the pharmacological benefits associated with niacin.

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“…The mechanisms of DGAT inhibition and TAG metabolism are active research area as more pharmacological drugs designs centering on the two DGAT enzymes (DGAT1 and DGAT2), which apparently have distinct and overlapping functions (Chitraju et al, 2019). Niacin was later found to be an important precursor of cofactor NAD + , which promotes SIRT/PGC-1α activity and thus modulates mitochondrial energy homeostasis, biogenesis, and lipid metabolism (Kirkland and Meyer-Ficca, 2018;Romani et al, 2019). Moreover, niacin provides vascular benefits through NAD + /SIRT mediated mechanism during endothelial lipotoxicity (Hughes-Large et al, 2014).…”

Section: Mitochondrial Bioenergetics and Biogenesis-promoting Agentsmentioning

confidence: 99%

Dyslipidemia in Kidney Disorders: Perspectives on Mitochondria Homeostasis and Therapeutic Opportunities

Lin

Duann

2020

Front. Physiol.

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To excrete body nitrogen waste and regulate electrolyte and fluid balance, the kidney has developed into an energy factory with only second to the heart in mitochondrial content in the body to meet the high-energy demand and regulate homeostasis. Energy supply from the renal mitochondria majorly depends on lipid metabolism, with programed enzyme systems in fatty acid β-oxidation and Krebs cycle. Renal mitochondria integrate several metabolic pathways, including AMPK/PGC-1α, PPARs, and CD36 signaling to maintain energy homeostasis for dynamic and static requirements. The pathobiology of several kidney disorders, including diabetic nephropathy, acute and chronic kidney injuries, has been primarily linked to impaired mitochondrial bioenergetics. Such homeostatic disruption in turn stimulates a pathological adaptation, with mitochondrial enzyme system reprograming possibly leading to dyslipidemia. However, this alteration, while rescuing oncotic pressure deficit secondary to albuminuria and dissipating edematous disorder, also imposes an ominous lipotoxic consequence. Reprograming of lipid metabolism in kidney injury is essential to preserve the integrity of kidney mitochondria, thereby preventing massive collateral damage including excessive autophagy and chronic inflammation. Here, we review dyslipidemia in kidney disorders and the most recent advances on targeting mitochondrial energy metabolism as a therapeutic strategy to restrict renal lipotoxicity, achieve salutary anti-edematous effects, and restore mitochondrial homeostasis.

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Niacin: an old lipid drug in a new NAD+ dress

Cited by 51 publications

References 66 publications

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

Nicotinamide attenuates the decrease in dendritic spine density in hippocampal primary neurons from 5xFAD mice, an Alzheimer’s disease animal model

The Role of GPR109a Signaling in Niacin Induced Effects on Fed and Fasted Hepatic Metabolism

Dyslipidemia in Kidney Disorders: Perspectives on Mitochondria Homeostasis and Therapeutic Opportunities

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