Quercetin and Genes


Quercetin Extends Lifespan in C. Elegans

Q uercetin, caffeic- and rosmarinic acid exposure extend lifespan in the simple roundworm Caenorhabditis elegans. A recent comparative study uncovered basic common and contrasting underlying mechanisms: For all three compounds, life extension was characterized by hormetic dose response curves, but levels of heat-shock-protein genes expression were variable.1 Hormesis is a phenomenon characterized by low dose stimulation and high dose inhibition.

Quercetin and rosmarinic acid both suppressed bacterial growth; however, antibacterial properties were not the dominant reason for life extension. Exposure to quercetin, caffeic- and rosmarinic acid resulted in reduced body size, altered lipid-metabolism and a tendency towards a delay in reproductive timing; however the total number of offspring was not affected.

An indirect dietary restriction effect, provoked by either chemo-repulsion or diminished pharyngeal pumping was rejected. Quercetin and Caffeic acid were shown to increase the antioxidative capacity in vivo and, by means of a lipofuscin assay, reduce the oxidative damage in the nematodes. Finally, it was possible to demonstrate that the life and thermotolerance enhancing properties of caffeic- and rosmarinic acid both rely on certain genes in the case of caffeic acid. Taken together, hormesis, in vivo antioxidative/prooxidative properties, modulation of genetic players, as well as the re-allocation of energy all contribute (to some extent and dependent on the polyphenol) to life extension.


Quercetin and Caffeic acid were
shown to increase the antioxidative
capacity in vivo and, by means of a
lipofuscin assay, reduce the oxidative
damage in the nematodes.


Quercetin Prolongs Lifespan in Mice

Following up on how quercetin may prolong lifespan in higher species, researchers from several aging universities and research centers have taken note that the health span of mice is enhanced by killing senescent cells using a transgenic suicide gene.2 A drug and a nutrient targeting the pro-survival networks in senescent cells selectively killed senescent cells.

Dasatinib, a cancer drug, eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse mesenchymal stem cells, multipotent connective tissue cells that can differentiate into a variety of cell types. In the study, of 46 agents tested, dasatinib and quercetin showed particular promise in clearing senescent cells.

References

1. Pietsch K1, Saul N, Chakrabarti S, et al. Hormetins, antioxidants and prooxidants: defining quercetin-, caffeic acid- and rosmarinic acid-mediated life extension in C. elegans. Biogerontology. 2011 Aug;12(4):329–47.
2. Zhu Y, Tchkonia T, Pirtskhalava T, et asl. The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs. Aging Cell. 2015 Mar 9. doi: 10.1111/acel.12344. [Epub ahead of print].


Quercetin Decreases High-Fat Diet
Induced Body Weight Gain

D ietary flavonoids may protect against cardiovascular diseases (CVD). Increased circulating lipid levels and hepatic lipid accumulation are known risk factors for CVD. The aim of this study was to investigate the effects and underlying molecular mechanisms of the flavonoid quercetin on hepatic lipid metabolism in mice with high-fat diet induced body weight gain and hepatic lipid accumulation. Adult male mice received a 40 energy% high-fat diet without or with supplementation of 0.33 % quercetin for 12 weeks. Body weight gain was 29 % lower in quercetin fed mice, while the energy intake was not significantly different.


Quercetin decreased high-fat diet
induced body weight gain,
hepatic lipid accumulation and
serum lipid levels.


Regulation of Cytochrome P450 2b Genes

Quercetin supplementation lowered hepatic lipid accumulation to 29 % of the amount present in the control mice. (1)H nuclear magnetic resonance serum lipid profiling revealed that the supplementation significantly lowered serum lipid levels. Global gene expression profiling of liver showed that cytochrome P450 2b (Cyp2b) genes, key target genes of the transcription factor constitutive androstane receptor, were downregulated. Quercetin decreased high-fat diet induced body weight gain, hepatic lipid accumulation and serum lipid levels. This was accompanied by regulation of cytochrome P450 2b genes in liver, which are possibly under transcriptional control of CAR. The quercetin effects are likely dependent on the fat content of the diet.


The quercetin effects
are likely dependent on the fat
content of the diet.


Reference

1. Hoek-van den Hil EF, van Schothorst EM, van der Stelt I, et al. Quercetin decreases high-fat diet induced body weight gain and accumulation of hepatic and circulating lipids in mice. Genes Nutr. 2014 Sep;9(5):418. doi: 10.1007/s12263-014-0418-2. Epub 2014 Jul 22.


Quercetin: More Effective Anti-Diabetic
than Anti-Obesity Biomolecule

Q uercetin exhibits a wide range of biological functions. The first aim of the present work was to analyze the effects of quercetin on fat accumulation in adipose tissue and glycemic control in rats. Any potential involvement of muscle fatty acid oxidation in its effect on glycemic control was also assessed. Animals were fed a high-fat high-sucrose diet either supplemented with quercetin (30 mg/kg body weight/day), or not supplemented, for 6 weeks.

Analyzed: The Expression of Several Genes

One week before sacrifice, a glucose tolerance test was carried out. Muscle triacylglycerol content, serum glucose, insulin, fructosamine and free fatty acids were measured, and homeostatic model assessment for insulin resistance (HOMA-IR) was calculated. The activities of lipogenic enzymes and lipoprotein lipase in adipose tissue, carnitine palmitoyl transferase-1b (CPT-1b) and citrate synthase in skeletal muscle, and the expression of several genes in skeletal muscle were analyzed.


Fructosamine, basal glucose and
insulin, and consequently HOMA-IR,
were significantly
reduced by quercetin.


Quercetin caused no significant reduction in body weight or adipose tissue sizes. However, fructosamine, basal glucose and insulin, and consequently HOMA-IR, were significantly reduced by quercetin. No changes were observed in the activity of lipogenic enzymes and lipoprotein lipase. Muscle triacylglycerol content was similar in both experimental groups. The expression of the genes remained unchanged. It can be concluded that quercetin is more effective as an anti-diabetic than as an anti-obesity biomolecule. The improvement in insulin resistance induced by this flavonoid is not mediated by a delipidating effect in skeletal muscle.


It can be concluded that quercetin is
more effective as an anti-diabetic
than as an anti-obesity biomolecule.


Reference

1. Arias N1, Macarulla MT, Aguirre L, et al. Quercetin can reduce insulin resistance without decreasing adipose tissue and skeletal muscle fat accumulation. Genes Nutr. 2014 Jan;9(1):361. doi: 10.1007/s12263-013-0361-7. Epub 2013 Dec 14.


Quercetin Increases Insulin Sensitivity
and Improves Glucose Tolerance

L ow doses of the flavonoid, quercetin, increase insulin sensitivity and improve glucose tolerance. In a new study, researchers hypothesized that dietary supplementation with red onion extract (RO)—which contains relatively high levels of quercetin—would reduce high fat diet (HFD)-induced obesity and insulin resistance similar to quercetin supplementation by increasing energy expenditure through a mechanism involving skeletal muscle mitochondrial adaptations.


Only HF + Q showed an increase in
physical activity levels.


To test this hypothesis, C57BL/6J mice—genetically modified mice often used as models of human disease—were randomized into four groups and fed either a low fat diet (LF), a high fat diet (HF), a high fat diet + quercetin (HF + Q), or a high fat diet + RO (HF + RO) for 9 weeks. Food consumption and body weight and composition were measured weekly. Insulin sensitivity was assessed by insulin and glucose tolerance tests. Energy expenditure and physical activity were measured by indirect calorimetry. Skeletal muscle incomplete beta oxidation, mitochondrial number, and mtDNA-encoded gene expression were measured.


Only HF + Q exhibited consistently
lower mRNA levels of mtDNA-
encoded genes necessary for
complexes IV and V compared to LF.


Lower mRNA Levels of mtDNA-Encoded Genes

Quercetin and RO supplementation decreased HFD-induced fat mass accumulation and insulin resistance (measured by insulin tolerance test) and increased energy expenditure; however, only HF + Q showed an increase in physical activity levels. Although quercetin and RO similarly increased skeletal muscle mitochondrial number and decreased incomplete beta oxidation, establishing mitochondrial function similar to that seen in LF, only HF + Q exhibited consistently lower mRNA levels of mtDNA-encoded genes necessary for complexes IV and V compared to LF. Quercetin- and RO-induced improvements in adiposity, insulin resistance, and energy expenditure occur through differential mechanisms, with quercetin—but not RO-induced energy expenditure being related to increases in physical activity. While both treatments improved skeletal muscle mitochondrial number and function, mtDNA-encoded transcript levels suggest that the antiobesogenic, insulin-sensitizing effects of purified quercetin aglycone, and RO may occur through differential mechanisms. Supplemental quercetin is more beneficial than the food that contains high amounts of it.


Supplemental quercetin is more
beneficial than the food that contains
high amounts of it.


Reference

1. Henagan TM, Cefalu WT, Ribnicky DM, et al. In vivo effects of dietary quercetin and quercetin-rich red onion extract on skeletal muscle mitochondria, metabolism, and insulin sensitivity. Genes Nutr. 2015 Jan;10(1):451–63.


Quercetin Exhibit Cardioprotective Properties
Through the Antiatherogenic Gene PON1

W hile the effects of chronic ethanol consumption on liver have been well studied and documented, its effect on the cardiovascular system may be positive or negative. Thus, moderate drinking in many population studies is related to lower prevalence of coronary artery disease (CAD). Yet, heavy drinking correlates with higher prevalence of CAD. In several other studies of cardiovascular mortalities, abstainers and heavy drinkers are at higher risk than light or moderate drinkers.

The composite of this disparate relation in several population studies of cardiovascular mortality has been a “U-” or “J-”shaped curve. Apart from its ability to eliminate cholesterol from the intima of the arteries by reverse cholesterol transport, another major mechanism by which HDL may have this cardioprotective property is by virtue of the ability of its component enzyme paraoxonase1 (PON1) to inhibit LDL oxidation and/or inactivate oxidized LDL (OxLDL).


Significantly, apart from its alcohol
content, red wine also has
polyphenols such as quercetin and
resveratrol that are also known to
have cardioprotective effects.


Therefore, PON1 plays a central role in the disposal of OxLDL and thus is antiatherogenic. Furthermore, PON1 is a multifunctional antioxidant enzyme that can also detoxify the homocysteine metabolite, homocysteine thiolactone (HTL), which can pathologically cause protein damage by homocysteinylation of the lysine residues, thereby leading to atherosclerosis.

Regulating the PON1 Gene

We demonstrated that moderate alcohol up regulates liver PON1 gene expression and serum activity, whereas heavy alcohol consumption had the opposite effects in both animal models and in humans. The increase in PON1 activity in light drinkers was not due to preferential distribution of high PON1 genotype in this group.


Quercetin also up regulates PON1
gene in rats and in human liver cells.


It is well known that wine consumption in several countries shows a remarkable inverse correlation to local rates of CAD mortality. Significantly, apart from its alcohol content, red wine also has polyphenols such as quercetin and resveratrol that are also known to have cardioprotective effects.

We have shown that quercetin also up regulates PON1 gene in rats and in human liver cells. The action of quercetin seems to be mediated via the active form of the nuclear lipogenic transcription factor, sterol-regulatory element-binding protein 2 (SREBP2) that is translocated from endoplasmic reticulum to the nucleus. However, the mechanism of action of ethanol-mediated up-regulation of PON1 gene remains to be elucidated.


Both moderate ethanol and quercetin,
the two major components of red
wine, exhibit cardioprotective
properties via the up-regulation of the
antiatherogenic gene PON1.


We conclude that both moderate ethanol and quercetin, the two major components of red wine, exhibit cardioprotective properties via the up-regulation of the antiatherogenic gene PON1.

Reference

1. Lakshman R, Garige M, Gong M, et al. Is alcohol beneficial or harmful for cardioprotection? Genes Nutr. 2010 Jun;5(2):111-20. doi: 10.1007/s12263-009-0161-2.


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