Additive Effects of Drinking Habits and a Susceptible Genetic Polymorphism on Cholesterol Efflux Capacity.

AIMS: High levels of high-density lipoprotein cholesterol (HDL-C) are not necessarily effective in preventing atherosclerotic cardiovascular disease, and cholesterol efflux capacity (CEC) has attracted attention regarding HDL functionality. We aimed to elucidate whether drinking habits are associated with CEC levels, while also paying careful attention to confounding factors including serum HDL-C levels, other life style factors, and rs671 (＊2), a genetic polymorphism of the aldehyde dehydrogenase 2 (ALDH2) gene determining alcohol consumption habit. METHODS: A cross-sectional study was performed in 505 Japanese male subjects who were recruited from a health screening program. Associations of HDL-C and CEC levels with drinking habits and ALDH2 genotypes were examined. RESULTS: The genotype frequencies of ALDH2 ＊1/＊1 (homozygous wild-type genotype), ＊1/＊2 and ＊2/＊2 (homozygous mutant genotype) were 55%, 37% and 8%, respectively. Both HDL-C and CEC levels were higher in ALDH2 ＊1/＊1 genotype carriers than in ＊2 allele carriers. Although HDL-C levels were higher in subjects who had a drinking habit than in non-drinkers, CEC levels tended to be lower in subjects with ≥ 46 g/day of alcohol consumption than in non-drinkers. Furthermore, CEC levels tended to be lower in ALDH2 ＊1/＊1 genotype carriers with a drinking habit of ≥ 46 g/day than non-drinkers, while for ＊2 allele carriers, CEC levels tended to be lower with a drinking habit of 23-45.9 g/day compared to no drinking habit. CONCLUSIONS: Our results suggest that heavy drinking habits may tend to decrease CEC levels, and in the ALDH2 ＊2 allele carriers, even moderate drinking habits may tend to decrease CEC levels.

Identification of Inhibitory Activities of Dietary Flavonoids against URAT1, a Renal Urate Re-Absorber: In Vitro Screening and Fractional Approach Focused on Rooibos Leaves.

Hyperuricemia, a lifestyle-related disease characterized by elevated serum urate levels, is the main risk factor for gout; therefore, the serum urate-lowering effects of human diets or dietary ingredients have attracted widespread interest. As Urate transporter 1 (URAT1) governs most urate reabsorption from primary urine into blood, URAT1 inhibition helps decrease serum urate levels by increasing the net renal urate excretion. In this study, we used a cell-based urate transport assay to investigate the URAT1-inhibitory effects of 162 extracts of plant materials consumed by humans. Among these, we focused on Aspalathus linearis, the source of rooibos tea, to explore its active ingredients. Using liquid-liquid extraction with subsequent column chromatography, as well as spectrometric analyses for chemical characterization, we identified quercetin as a URAT1 inhibitor. We also investigated the URAT1-inhibitory activities of 23 dietary ingredients including nine flavanols, two flavanonols, two flavones, two isoflavonoids, eight chalcones, and a coumarin. Among the tested authentic chemicals, fisetin and quercetin showed the strongest and second-strongest URAT1-inhibitory activities, with IC50 values of 7.5 and 12.6 µM, respectively. Although these effects of phytochemicals should be investigated further in human studies, our findings may provide new clues for using nutraceuticals to promote health.

Soy Isoflavone Genistein Inhibits an Axillary Osmidrosis Risk Factor ABCC11: In Vitro Screening and Fractional Approach for ABCC11-Inhibitory Activities in Plant Extracts and Dietary Flavonoids.

Axillary osmidrosis (AO) is a common chronic skin condition characterized by unpleasant body odors emanating from the armpits, and its aetiology is not fully understood. AO can seriously impair the psychosocial well-being of the affected individuals; however, no causal therapy has been established for it other than surgical treatment. Recent studies have revealed that human ATP-binding cassette transporter C11 (ABCC11) is an AO risk factor when it is expressed in the axillary apocrine glands-the sources of the offensive odors. Hence, identifying safe ways to inhibit ABCC11 may offer a breakthrough in treating AO. We herein screened for ABCC11-inhibitory activities in 34 natural products derived from plants cultivated for human consumption using an in vitro assay system to measure the ABCC11-mediated transport of radiolabeled dehydroepiandrosterone sulfate (DHEA-S-an ABCC11 substrate). The water extract of soybean (Glycine max) was found to exhibit the strongest transport inhibition. From this extract, via a fractionation approach, we successfully isolated and identified genistein, a soy isoflavone, as a novel ABCC11 inhibitor with a half-maximal inhibitory concentration value of 61.5 µM. Furthermore, we examined the effects of other dietary flavonoids on the ABCC11-mediated DHEA-S transport to uncover the effects of these phytochemicals on ABCC11 function. While further human studies are needed, our findings here about the natural compounds will help develop a non-surgical therapy for AO.

Omega-3 Polyunsaturated Fatty Acids Inhibit the Function of Human URAT1, a Renal Urate Re-Absorber.

The beneficial effects of fatty acids (FAs) on human health have attracted widespread interest. However, little is known about the impact of FAs on the handling of urate, the end-product of human purine metabolism, in the body. Increased serum urate levels occur in hyperuricemia, a disease that can lead to gout. In humans, urate filtered by the glomerulus of the kidney is majorly re-absorbed from primary urine into the blood via the urate transporter 1 (URAT1)-mediated pathway. URAT1 inhibition, thus, contributes to decreasing serum urate concentration by increasing net renal urate excretion. Here, we investigated the URAT1-inhibitory effects of 25 FAs that are commonly contained in foods or produced in the body. For this purpose, we conducted an in vitro transport assay using cells transiently expressing URAT1. Our results showed that unsaturated FAs, especially long-chain unsaturated FAs, inhibited URAT1 more strongly than saturated FAs. Among the tested unsaturated FAs, eicosapentaenoic acid, α-linolenic acid, and docosahexaenoic acid exhibited substantial URAT1-inhibitory activities, with half maximal inhibitory concentration values of 6.0, 14.2, and 15.2 µM, respectively. Although further studies are required to investigate whether the ω-3 polyunsaturated FAs can be employed as uricosuric agents, our findings further confirm FAs as nutritionally important substances influencing human health.

Inhibitory effect of Citrus flavonoids on the in vitro transport activity of human urate transporter 1 (URAT1/SLC22A12), a renal re-absorber of urate.

As hyperuricemia is a cause of urate-related diseases such as gout, the anti-hyperuricemic and/or uricosuric activity of food ingredients is receiving increased attention. Here, we examined the inhibitory activities of seven Citrus flavonoids against URAT1, a renal transporter involved in urate re-uptake from urine. We found that naringenin and nobiletin strongly inhibited URAT1, and may therefore serve as an anti-hyperuricemic food ingredient that can reduce the risk of urate-related diseases.

Comprehensive analysis of mechanism underlying hypouricemic effect of glucosyl hesperidin.

Hyperuricemia is caused by hepatic overproduction of uric acid and/or underexcretion of urate from the kidneys and small intestine. Although increased intake of citrus fruits, a fructose-rich food, is associated with increased risk of gout in humans, hesperidin, a flavonoid naturally present in citrus fruits, reportedly reduces serum uric acid (SUA) levels by inhibiting xanthine oxidase (XOD) activity in rats. However, the effects of hesperidin on renal and intestinal urate excretion were previously unknown. In this study, we used glucosyl hesperidin (GH), which has greater bioavailability than hesperidin, to clarify comprehensive mechanisms underlying the hypouricemic effects of hesperidin in vivo. GH dose-dependently decreased SUA levels in mice with hyperuricemia induced by potassium oxonate and a fructose-rich diet, and inhibited XOD activity in the liver. GH decreased renal urate excretion without changes in kidney URAT1, ABCG2 or GLUT9 expressions, suggesting that reducing uric acid pool size by inhibiting XOD decreased renal urate excretion. We also found that GH had no effect on intestinal urate excretion or protein expression of ABCG2. Therefore, we concluded that GH exhibits a hypouricemic effect by inhibiting XOD activity in the liver without increasing renal or intestinal urate excretion. Of note, this is the first study to elucidate the effect of a flavonoid on intestinal urate excretion using a mice model, whose findings should prove useful in future food science research in the area of urate metabolism. Taking these findings together, GH may be useful for preventing hyperuricemia, especially in people with the overproduction type.