Epigallocatechin gallate (EGCG) is the most abundant polyphenolic flavonoid in green tea. Catechin and its derivatives, including EGCG, are widely believed to function as antioxidants. Here we demonstrate that both EGCG and green tea extract (GTE) cause oxidative stress-related responses in the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe under weak alkaline conditions in terms of the activation of oxidative-stress-responsive transcription factors. GTE as well as EGCG induced the nuclear localization of Yap1 in S. cerevisiae, which was repressed by the addition of catalase but not by the addition of superoxide dismutase. The same phenomena were observed for the nucleocytoplasmic localization of Msn2 in S. cerevisiae and Pap1, a Yap1 homologue, in S. pombe. The formation of intramolecular disulfide bonds has been proposed to be crucial for the H 2 O 2 -induced nuclear localization of Yap1, and we verified the importance of cysteine residues of Yap1 in response to EGCG and GTE. Additionally, we show that EGCG and GTE produce H 2 O 2 in a weak alkaline medium. Finally, we conclude that tea polyphenols are able to act as prooxidants to cause a response to oxidative stress in yeasts under certain conditions.Green tea is one of the beverages consumed in the highest quantity in the world. Epidemiologic research has revealed that individuals who drink a lot of green are less likely to develop cancer (28,30,51,64). Very recently, a relationship between the consumption of green tea and a reduced risk of type 2 diabetes was reported (23). Green tea contains many ingredients considered to promote health such as polyphenolic flavonoids, of which epigallocatechin gallate (EGCG) is the major constituent. Evidence is mounting that EGCG has anticarcinogenic activity in vitro (3,8,27,61), which may support the results of the epidemiologic research on the correlation between drinking green tea and the risk of morbidity from cancer.Many studies have been done on the biological activity of green tea extract (GTE) and individual catechins in vitro. EGCG is widely accepted as an antioxidant. For example, EGCG scavenges superoxide anion radicals (O 2 ·Ϫ ), hydrogen peroxide (H 2 O 2 ), hydroxy radicals (HO · ), peroxyl radicals, singlet oxygen, and peroxynitrite (5,16,17,45,47,49,56). The one-electron reduction potential of EGCG under standard conditions is 550 mV, a value lower than that of glutathione (920 mV) and comparable to that of ␣-tocopherol (480 mV) (13,24,25). Besides directly scavenging reactive oxygen/nitrogen species, EGCG chelates redox-active metal ions, such as iron and copper, leading to a reduction in the production of reactive oxygen species. Accordingly, many food supplements or beverages containing a high concentration of EGCG (Ͼ1 mM) have been developed, and therefore, the physiological function of EGCG in vivo with a high-dose ingestion remains to be elucidated.In contrast to its antioxidative activity, recent experiments in vitro indicate that EGCG produces reactive oxy...

The glyoxalase system consists of glyoxalase I and glyoxalase II. Glyoxalase I catalyzes the conversion of methylglyoxal (CH(3)COCHO), a metabolite derived from glycolysis, with glutathione to S-D-lactoylglutathione, while glyoxalase II hydrolyses this glutathione thiolester to D-lactic acid and glutathione. Since methylglyoxal is toxic due to its high reactivity, the glyoxalase system is crucial to warrant the efficient metabolic flux of this reactive aldehyde. The budding yeast Saccharomyces cerevisiae has the sole gene (GLO1) encoding the structural gene for glyoxalase I. Meanwhile, this yeast has two isoforms of glyoxalase II encoded by GLO2 and GLO4. The expression of GLO1 is regulated by Hog1 mitogen-activated protein kinase and Msn2/Msn4 transcription factors under highly osmotic stress conditions. The physiological significance of GLO1 expression in response to osmotic stress is to combat the increase in the levels of methylglyoxal in cells during the production of glycerol as a compatible osmolyte. Deficiency in GLO1 in S. cerevisiae causes pleiotropic phenotypes in terms of stress response, because the steady state level of methylglyoxal increases in glo1Δ cells thereby constitutively activating Yap1 transcription factor. Yap1 is crucial for oxidative stress response, although methylglyoxal per se does not enhance the intracellular oxidation level in yeast, but it directly modifies cysteine residues of Yap1 that are critical for the nucleocytoplasmic localization of this b-ZIP transcription factor. Consequently, glyoxalase I can be defined as a negative regulator of Yap1 through modulating the intracellular methylglyoxal level.

Methylglyoxal is a typical 2-oxoaldehyde derived from glycolysis. We show here that methylglyoxal activates the Pkc1-Mpk1 mitogen-activated protein (MAP) kinase cascade in a target of rapamycin complex 2 (TORC2)-dependent manner in the budding yeast Saccharomyces cerevisiae.

Obesity causes excess fat accumulation in white adipose tissues (WAT) and also in other insulin-responsive organs such as the skeletal muscle, increasing the risk for insulin resistance, which can lead to obesity-related metabolic disorders. Peroxisome proliferator-activated receptor-α (PPARα) is a master regulator of fatty acid oxidation whose activator is known to improve hyperlipidemia. However, the molecular mechanisms underlying PPARα activator-mediated reduction in adiposity and improvement of metabolic disorders are largely unknown. In this study we investigated the effects of PPARα agonist (fenofibrate) on glucose metabolism dysfunction in obese mice. Fenofibrate treatment reduced adiposity and attenuated obesity-induced dysfunctions of glucose metabolism in obese mice fed a high-fat diet. However, fenofibrate treatment did not improve glucose metabolism in lipodystrophic A-Zip/F1 mice, suggesting that adipose tissue is important for the fenofibrate-mediated amelioration of glucose metabolism, although skeletal muscle actions could not be completely excluded. Moreover, we investigated the role of the hepatokine fibroblast growth factor 21 (FGF21), which regulates energy metabolism in adipose tissue. In WAT of WT mice, but not of FGF21-deficient mice, fenofibrate enhanced the expression of genes related to brown adipocyte functions, such as ,, and Fenofibrate increased energy expenditure and attenuated obesity, whole body insulin resistance, and adipocyte dysfunctions in WAT in high-fat-diet-fed WT mice but not in FGF21-deficient mice. These findings indicate that FGF21 is crucial for the fenofibrate-mediated improvement of whole body glucose metabolism in obese mice via the amelioration of WAT dysfunctions.

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SummaryThe mevalonate pathway is essential for the synthesis of isoprenoids and cholesterol. Adipose tissue is known as a major site for cholesterol storage; however, the role of the local mevalonate pathway and its synthesized isoprenoids remains unclear. In this study, adipose-specific mevalonate pathway-disrupted (aKO) mice were generated through knockout of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (HMGCR). aKO mice showed serious lipodystrophy accompanied with glucose and lipid metabolic disorders and hepatomegaly. These metabolic variations in aKO mice were dramatically reversed after fat transplantation. In addition, HMGCR-disrupted adipocytes exhibited loss of lipid accumulation and an increase of cell death, which were ameliorated by the supplementation of mevalonate and geranylgeranyl pyrophosphate but not farnesyl pyrophosphate and squalene. Finally, we found that apoptosis may be involved in adipocyte death induced by HMGCR down-regulation. Our findings indicate that the mevalonate pathway is essential for adipocytes and further suggest that this pathway is an important regulator of adipocyte turnover.

Background: Methylglyoxal is a typical 2-oxoaldehyde derived from glycolysis. Results: Methylglyoxal inhibited the activity of yeast hexose transporters as well as mammalian glucose transporters (GLUT1 and GLUT4) and enhanced the endocytosis of hexose transporters in yeast. Conclusion: Methylglyoxal inhibited glucose uptake in yeast cells. Significance: Phospholipase C and protein kinase C were involved in endocytosis of hexose transporters.

These findings indicate that synthesized enone fatty acids show potent anti-inflammatory effects, leading to the improvement of inflammation-induced dysfunctions in adipocytes.