Functional Impact of the FADS1 rs174546 Single Nucleotide Polymorphism on Serum Lipid Levels: Insights from Molecular Mechanisms and Therapeutic Perspectives in Korean Population.

SCOPE: Single nucleotide polymorphisms (SNP) in the fatty acid desaturase 1 (FADS1) gene is suggested as risk factor of metabolic diseases in genome-wide association studies (GWAS). This study hypothesized that FADS1_rs174546T associates with serum triglycerides (TG) in Korean Genome and Epidemiology Study (KoGES). In addition, functional study of SNP genotypes in cultured cells is performed. METHODS AND RESULTS: FADS1_rs174546T is associated with high level of serum TG (effect size of variant: 6.48 ± 1.84 mg dL-1) in Korean individuals (normotriglyceridemia, n = 5128; hypertriglyceridemia, n = 3714). Functional study in cells with FADS1_rs174546T, shows reduced transcriptional activity, when compared with rs174546C. MiR-6728-3p, which is predicted to bind with rs174546T, decreases transcriptional activity of rs174546T but not in rs174546C, and it is reversed by miR-6728-3p inhibitor. Formononetin is selected as binding molecule to 3'-UTR of FADS1 and increases luciferase activity in both rs174546 (C/T). Moreover, formononetin compensates for the reduced luciferase activity by rs174546T and miR-6728-3p. Formononetin also increases endogenous FADS1 expression and long-chain polyunsaturated fatty acid (LC-PUFA) ratio. CONCLUSION: FADS1_rs174546T is a crucial risk factor for hypertriglyceridemia in the Koreans potentially through the interaction with miR-6728-3p. Formononetin can be a potent dietary intervention to prevent and improve hypertriglyceridemia in both rs174546 (C/T) populations.

Traditional Korean diet high in one-carbon nutrients increases global DNA methylation: implication for epigenetic diet.

PURPOSE: DNA methylation is a major epigenetic phenomenon through which diet affects health and disease. This study aimed to determine the epigenetic influence of the traditional Korean diet (K-diet) on global DNA methylation via one-carbon metabolism. METHODS: A crossover study was conducted on 52 women. Two diets, a K-diet, high in plant foods and low in calories and animal fat, and a control diet, similar to the diet currently consumed in Korea, were provided to all subjects alternately for 4 weeks with a 4-week washout period. Clinical parameters were measured before and after each dietary intervention. Nutrient intake was calculated by using a computer-aided nutritional analysis program. One-carbon metabolites in the serum and global DNA methylation in peripheral mononuclear cells were determined using ultra-performance liquid chromatography-tandem mass spectrometry. RESULTS: The K-diet group consumed more folate (669.9 ± 6.7 µg vs. 502.7 ± 3.0, p < 0.001), B6, B12, serine, and choline, and less methionine (992.6 ± 63 vs. 1048.3 mg ± 34.1, p < 0.0001) than the control group did. In the K-diet group, the increment of plasma 5-methyltetrahydrofolate (0.08 µg/mL ± 0.11 vs 0.02 ± 0.10, p < 0.009) and decrement of L-homocysteine (- 70.7 ± 85.0 vs - 39.3 ± 69.4, p < 0.0168) were greater than those of the control group. Global DNA methylation was significantly increased in the K-diet group (6.70 ± 3.02% to 9.45 ± 3.69, p < 0.0001) but not in the control group. CONCLUSIONS: A K-diet high in one-carbon nutrients can enhance the global DNA methylation status, suggesting an epigenetic mechanism by which the K-diet conveys health effects. Trial registration Korean Clinical Trial Registry (trial number: KCT0005340, 24/08/2020, retrospectively registered).

Interaction of energy and sulfur microbial diet and smoking status with polygenic variants associated with lipoprotein metabolism.

Introduction: Hypo-high-density lipoprotein cholesterolemia (hypo-HDL-C) contributes to the development of cardiovascular diseases. The hypothesis that the polygenic variants associated with hypo-HDL-C interact with lifestyle factors was examined in 58,701 middle-aged Korean adults who participated in the Korean Genome and Epidemiology Study (KoGES). Methods: Participants were categorized into the Low-HDL (case; n = 16,980) and Normal-HDL (n = 41,721) groups. The participants in the Low-HDL group were selected using the guideline-based cutoffs for hypo-HDL-C (<40 mg/dL for men and < 50 mg/dL for women) and included those taking medication for dyslipidemia. The genes associated with hypo-HDL-C were determined through a genome-wide association study (GWAS) in a city hospital-based cohort, and the results were validated in the Ansan/Anung study. The genetic variants for the single nucleotide polymorphism (SNP)-SNP interaction were selected using a generalized multifactor dimensionality reduction analysis, and the polygenic risk score (PRS) generated was evaluated for interaction with lifestyle parameters. Results: The participants with hypo-HDL-C showed a 1.45 and 1.36-fold higher association with myocardial infarction and stroke, respectively. The High-PRS with four SNPs, namely ZPR1_rs3741297, CETP_rs708272, BUD13_rs180327, and ALDH1A2_rs588136, and that with the 11q23.3 haplotype were positively associated with hypo-HDL-C by about 3 times, which was a 2.4-fold higher association than the PRS of 24 SNP with p < 5×10-8. The risk alleles of CETP_rs708272 and ALDH1A2_rs588136 were linked to increased expression in the heart and decreased in the brain, respectively. The selected SNPs were linked to the reverse cholesterol transport pathway, triglyceride-rich lipoprotein particle remodeling pathway, cholesterol storage, and macrophage-derived foam cell differentiation regulation. The PRS of the 4-SNP model interacted with energy intake and smoking status, while that of the haplotype interacted with a glycemic index of the diet, sulfur microbial diet, and smoking status. Discussion: Adults with a genetic risk for hypo-HDL-C need to modulate their diet and smoking status to reduce their risk.

Association of Polygenic Variants with Type 2 Diabetes Risk and Their Interaction with Lifestyles in Asians.

Over the last several decades, there has been a considerable growth in type 2 diabetes (T2DM) in Asians. A pathophysiological mechanism in Asian T2DM is closely linked to low insulin secretion, ß-cell mass, and inability to compensate for insulin resistance. We hypothesized that genetic variants associated with lower ß-cell mass and function and their combination with unhealthy lifestyle factors significantly raise T2DM risk among Asians. This hypothesis was explored with participants aged over 40. Participants were categorized into T2DM (case; n = 5383) and control (n = 53,318) groups. The genetic variants associated with a higher risk of T2DM were selected from a genome-wide association study in a city hospital-based cohort, and they were confirmed with a replicate study in Ansan/Ansung plus rural cohorts. The interacted genetic variants were identified with generalized multifactor dimensionality reduction analysis, and the polygenic risk score (PRS)-nutrient interactions were examined. The 8-SNP model was positively associated with T2DM risk by about 10 times, exhibiting a higher association than the 20-SNP model, including all T2DM-linked SNPs with p < 5 × 10−6. The SNPs in the models were primarily involved in pancreatic ß-cell growth and survival. The PRS of the 8-SNP model interacted with three lifestyle factors: energy intake based on the estimated energy requirement (EER), Western-style diet (WSD), and smoking status. Fasting serum glucose concentrations were much higher in the participants with High-PRS in rather low EER intake and high-WSD compared to the High-EER and Low-WSD, respectively. They were shown to be higher in the participants with High-PRS in smokers than in non-smokers. In conclusion, the genetic impact of T2DM risk was mainly involved with regulating pancreatic ß-cell mass and function, and the PRS interacted with lifestyles. These results highlight the interaction between genetic impacts and lifestyles in precision nutrition.

Beneficial Effects of a Low-Glycemic Diet on Serum Metabolites and Gut Microbiota in Obese Women With Prevotella and Bacteriodes Enterotypes: A Randomized Clinical Trial.

Generalized healthy eating patterns may not benefit everyone due to different genetics and enterotypes. We aimed to compare the effects of a low-glycemic diet representing the Korean traditional balanced diet (Low-GID) and westernized diet as a control diet (CD) on anthropometry, serum metabolites, and fecal bacteria in a randomized clinical trial according to enterotypes. We recruited 52 obese women aged 30-50 years, and they consumed Low-GID and CD meals for 1 month, with a 1-month washout period, in a crossover randomized clinical trial. The Low-GID was mainly composed of whole grains with fish, vegetables, seaweeds, and perilla oil, whereas CD contained refined rice, bread, noodles, meats, and processed foods. Serum lipid profiles, metabolomics, serum short-chain fatty acids, and fecal bacteria were analyzed. The important variables influenced by Low-GID and CD were determined by SHAP value in the XGBoost algorithm according to Bacteroides (ET-B) and Prevotella (ET-P). Low-GID and CD interventions did not change the enterotypes, but they modified serum metabolites and some fecal bacterial species differently according to enterotypes. The 10-fold cross-validation of the XGBoost classifier in the ET-P and ET-B clusters was 0.91 ± 0.04 and 0.8 ± 0.07, respectively. In the ET-P cluster, serum L-homocysteine, glutamate, leucine concentrations, and muscle mass were higher in the CD group than in the Low-GID group, whereas serum 3-hydroxybutyric acid concentration was significantly higher in the Low-GID group than in the CD group (p < 0.05). In fecal bacteria, Gemmiger formicilis, Collinsella aerofaciens, and Escherichia coli were higher in the CD group than in the Low-GID group. In the ET-B cohort, serum tryptophan and total cholesterol concentrations were higher in the CD group than in the Low-GID group, whereas serum glutathione and 3-hydroxybutyric acid concentrations were significantly higher in the Low-GID group than in the CD group (p < 0.05). However, Bifidobacterium longum was higher in CD than Low-GID in the ET-B cluster, but serum butyric acid levels were higher in the Low-GID than in the CD group. In conclusion, Low-GID can be recommended in obese women with both ET-P and ET-B enterotypes, although its efficacy was more effective in ET-P. Clinical Trial Registration: [https://cris.nih.go.kr/cris/search/detailSearch.do/17398], identifier [KCT0005340].

Alleviation of Dyslipidemia via a Traditional Balanced Korean Diet Represented by a Low Glycemic and Low Cholesterol Diet in Obese Women in a Randomized Controlled Trial.

A traditional balanced Korean diet (K-diet) may improve energy, glucose, and lipid metabolism. To evaluate this, we conducted a randomized crossover clinical trial, involving participants aged 30-40 years, who were randomly assigned to two groups-a K-diet or westernized Korean control diet daily, with an estimated energy requirement (EER) of 1900 kcal. After a 4-week washout period, they switched the diet and followed it for 4 weeks. The carbohydrate, protein, and fat ratios based on energy intake were close to the target values for the K-diet (65:15:20) and control diet (60:15:25). The glycemic index of the control diet and the K-diet was 50.3 ± 3.6 and 68.1 ± 2.9, respectively, and daily cholesterol contents in the control diet and K-diet were 280 and 150 mg, respectively. Anthropometric and biochemical parameters involved in energy, glucose, and lipid metabolism were measured while plasma metabolites were determined using UPLC-QTOF-MS before and after the 4-week intervention. After the four-week intervention, both diets improved anthropometric and biochemical variables, but the K-diet significantly reduced them compared to the control diet. Serum total cholesterol, non-high-density lipoprotein cholesterol, and triglyceride concentrations were significantly lower in the K-diet group than in the control diet group. The waist circumference (p = 0.108) and insulin resistance index (QUICKI, p = 0.089) tended to be lower in the K-diet group than in the control diet group. Plasma metabolites indicated that participants in the K-diet group tended to reduce insulin resistance compared to those in the control diet group. Amino acids, especially branched-chain amino acids, tyrosine, tryptophan, and glutamate, and L-homocysteine concentrations were considerably lower in the K-diet group than in the control diet group (p < 0.05). Plasma glutathione concentrations, an index of antioxidant status, and 3-hydroxybutyric acid concentrations, were higher in the K-diet group than in the control diet group. In conclusion, a K-diet with adequate calories to meet EER alleviated dyslipidemia by decreasing insulin resistance-related amino acids and increasing ketones in the circulation of obese women.

Luteolin improves hypercholesterolemia and glucose intolerance through LXRα-dependent pathway in diet-induced obese mice.

Luteolin, a naturally derived flavonoid, exerts beneficial effects such as antitumor, antioxidant, and anti-inflammatory effects. However, the molecular mechanism underlying the effect of luteolin in hypercholesterolemia remains unclear. In this study, we demonstrated that luteolin upregulated the expression of liver X receptor (LXR) α, ATP-binding cassette transporter G1 (ABCG1), and scavenger receptor class B member 1 (SRB1), which play a major role in cholesterol efflux, in HepG2 hepatocytes. Luteolin-stimulated expression of ABCG1 and SRB1 was reversed by inhibitory compound of LXRα. Luteolin administration also upregulated the expression of ABCG1, and SRB1 as well as cholesterol 7 α-hydroxylase (Cyp7α1) in the liver of diet-induced obese mice. Luteolin decreased the level of blood cholesterol and non-high-density lipoprotein cholesterol in obese mice. In addition, luteolin ameliorated glucose intolerance and reduced expression of gluconeogenesis-associated enzymes in an LXRα-dependent manner. PRACTICAL APPLICATIONS: Luteolin is known to possess various pharmacological activities. This research revealed that luteolin ameliorates hypercholesterolemia and glucose intolerance in diet-induced obesity. The results indicate that the potential properties of luteolin in cholesterol metabolism could be explained, at least in part, as being due to upregulated expression of ABCG1, and SRB1 through activation of liver X receptor, LXRα signaling pathway in HepG2 cells.

Soy milk digestion extract inhibits progression of prostate cancer cell growth via regulation of prostate cancer­specific antigen and cell cycle-regulatory genes in human LNCaP cancer cells.

Soy milk, which is produced from whole soybeans, contains a variety of biologically active components. Isoflavones are a class of soy-derived phytoestrogens with beneficial effects, among which genistein (GEN) has been previously indicated to reduce the risk of prostate cancer. The present study evaluated the effects of soy milk digestion extract (SMD) on the progression of prostate cancer via the estrogen receptor (ER)ß in human LNCaP prostate cancer cells. To evaluate the effects of SMD (daizein, 1.988 mg/100g, glycitein, 23.537 mg/100 g and GEN, 0.685 mg/100g) on cell proliferation, LNCaP cells were cultured in media containing vehicle (0.1% dimethyl sulfoxide), 17ß­estradiol (E2; 2.7x10­7 mg/ml), GEN (2.7x10-2 mg/ml) of SMD (total aglycon concentration, 0.79 mg/ml), after which the cell viability was examined using an MTT assay. The cell viability was significantly elevated by E2 (by 45±0.18%), while it was markedly reduced by GEN (73.2±0.03%) or SMD (74.8±0.09%). Semi­quantitative reverse transcription polymerase chain reaction analysis was performed to assess the mRNA expression levels of target genes, including ERß, prostate cancer­specific antigen (PSA) and cell cycle regulators p21, Cyclin D1 and cyclin-dependent kinase (CDK)4. The expression of ERß was almost completely diminished by E2, whereas it was significantly elevated by SMD. In addition, the expression levels of PSA were considerably reduced by SMD. The expression of p21 was significantly elevated by SMD, while it was markedly reduced by E2. Of note, the expression levels of Cyclin D1 and CDK4 were considerably elevated by E2, while being significantly reduced by GEN and SMD. All of these results indicated that SMD may inhibit the proliferation of human prostate cancer cells via regulating the expression of ERß, PSA, p21, Cyclin D1 and CDK4 in an ER-dependent manner.

Low-FODMAP formula improves diarrhea and nutritional status in hospitalized patients receiving enteral nutrition: a randomized, multicenter, double-blind clinical trial.

BACKGROUND: Fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) are poorly absorbed, short-chain carbohydrates that play an important role in inducing functional gut symptoms. A low-FODMAP diet improves abdominal symptoms in patients with inflammatory bowel disease and irritable bowel syndrome. However, there were no study for the effect of FODMAP content on gastrointestinal intolerance and nutritional status in patients receiving enteral nutrition (EN). METHODS: In this randomized, multicenter, double-blind, 14-day clinical trial, eligible hospitalized patients receiving EN (n = 100) were randomly assigned to three groups; 84 patients completed the trial (low-FODMAP EN, n = 30; moderate-FODMAP EN, n = 28; high-FODMAP EN, n = 26). Anthropometric and biochemical parameters were measured; stool assessment was performed using the King's Stool Chart and clinical definition. RESULTS: Baseline values were not significantly different among the three groups. After the 14-day intervention, diarrhea significantly improved in the low-FODMAP group than in the moderate- and high-FODMAP groups (P < 0.05). King's Stool scores in diarrhea subjects were significantly and steadily reduced in the low-FODMAP group compared with the other two groups (P for time and EN type interaction <0.05). BMI increased significantly in the low- and high-FODMAP groups during the intervention (P < 0.05 for both), and showed a trend toward increasing in the moderate-FODMAP group (P < 0.10). Serum prealbumin increased significantly in all groups by 14-day; by 3-day, it had increased to the levels at 14-day in the low-FODMAP group. At 14-day, serum transferrin had increased significantly in the moderate-FODMAP group. In addition, subjects were classified by final condition (unimproved, normal maintenance, diarrhea only improved, constipation only improved, and recurrent diarrhea/constipation improved). Seventy-five percent of the diarrhea improved group consumed the low-FODMAP EN formula. 38.5 and 46.2% of recurrent diarrhea/constipation improved group consumed the low- and moderate-FODMAP EN respectively. BMI significantly increased in all groups except the unimproved. Prealbumin levels significantly increased in the diarrhea-improved and recurrent diarrhea/constipation groups at 3-day and continued by 14-day, and in the constipation-improved group at 14-day. Transferrin levels significantly increased in the diarrhea-improved and recurrent diarrhea/constipation groups at 14-day. CONCLUSION: Low-FODMAP EN may improve diarrhea, leading to improved nutritional status and facilitating prompt recovery from illness.

Isoflavone supplementation influenced levels of triglyceride and luteunizing hormone in Korean postmenopausal women.

We conducted a double-blind, randomized, placebo-controlled trial to evaluate the effects of soy-derived isoflavone on blood glucose, lipid profiles, and sex hormones related to cardiovascular disease in Korean postmenopausal women. One hundred thirteen postmenopausal women were recruited from the Seoul metropolitan area. To confirm postmenopausal and gynecologic status, the subjects were clinically examined by a gynecologist using ultra sound and X-ray. Finally, 85 postmenopausal women whose follicle-stimulating hormone (FSH) levels were higher than 40 IU/ml were enrolled. Subjects received either 70 mg isoflavone or placebo capsules daily for 12 weeks. As a result, the values of fasting glucose, insulin and HOMA-IR, as well as those of TC, LDL-C, HDL-C and FFA, were not different between the groups after supplementation. However, triglyceride (TG) levels in the treatment group decreased significantly compared with those of the placebo group (p = 0.0215). The levels of luteinizing hormone (LH) significantly decreased in the treatment group (p = 0.027); however, the levels of FSH, estrone and estradiol were not changed after intervention. In conclusion, isoflavone supplement of 70 mg/day for 12 weeks decreased blood levels of TG and LH in Korean postmenopausal women.