Docosahexaenoic Acid Modulates Nonalcoholic Fatty Liver Disease by Suppressing Endocannabinoid System.

SCOPE: Endocannabinoid signaling regulates energy homeostasis, and is tightly associated with nonalcoholic fatty liver disease (NAFLD). The study previously finds that supplementation of docosahexaenoic acid (DHA) has superior function to ameliorate NAFLD compared with eicosapentaenoic acid (EPA), however, the underlying mechanism remains elusive. The present study aims to investigate whether DHA intervention alleviates NAFLD via endocannabinoid system. METHODS AND RESULTS: In a case-control study, the serum endocannabinoid ligands in 60 NAFLD and 60 healthy subjects are measured. Meanwhile, NAFLD model is established in mice fed a high-fat and -cholesterol diet (HFD) for 9 weeks. DHA or EPA is administrated for additional 9 weeks. Serum primary endocannabinoid ligands, namely anandamide (AEA) and 2-arachidoniylglycerol (2-AG), are significantly higher in individuals with NAFLD compared with healthy controls. NAFLD model shows that serum 2-AG concentrations and adipocyte cannabinoid receptor 1 expression levels are significantly lower in DHA group compared with HFD group. Lipidomic and targeted ceramide analyses further confirm that endocannabinoid signaling inhibition has exerted deletion of hepatic C16:0-ceramide contents, resulting in down-regulation of de novo fatty acid synthesis and up-regulation of fatty acid ß-oxidation related protein expression levels. CONCLUSIONS: This work elucidates that DHA has improved NAFLD by suppressing endocannabinoid system.

Effects of dietary supplementation of fish oil plus vitamin D3 on gut microbiota and fecal metabolites, and their correlation with nonalcoholic fatty liver disease risk factors: a randomized controlled trial.

We previously reported that fish oil plus vitamin D3 (FO + D) could ameliorate nonalcoholic fatty liver disease (NAFLD). However, it is unclear whether the beneficial effects of FO + D on NAFLD are associated with gut microbiota and fecal metabolites. In this study, we investigated the effects of dietary supplementation of FO + D on gut microbiota and fecal metabolites and their correlation with NAFLD risk factors. Methods: A total of 61 subjects were randomly divided into three groups: FO + D group (2.34 g day-1 of eicosatetraenoic acid (EPA) + docosahexaenoic acid (DHA) + 1680 IU vitamin D3), FO group (2.34 g day-1 of EPA + DHA), and corn oil (CO) group (1.70 g d-1 linoleic acid). Blood and fecal samples were collected at the baseline and day 90. Gut microbiota were analyzed through 16S rRNA PCR analysis, and fecal co-metabolites were determined via untargeted ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Results: The relative abundance of Eubacterium (p = 0.03) and Lactobacillus (p = 0.05) increased, whereas that of Streptococcus (p = 0.02) and Dialister (p = 0.04) decreased in the FO + D group compared with the CO group. Besides, changes in tetracosahexaenoic acid (THA, C24:6 n-3) (p = 0.03) levels were significantly enhanced, whereas 8,9-DiHETrE levels (p < 0.05) were reduced in the FO + D group compared with the CO group. The changes in 1,25-dihydroxyvitamin D3 levels in the fecal samples were inversely associated with insulin resistance, which was determined using the homeostatic model assessment model (HOMA-IR, r = -0.29, p = 0.02), and changes in 8,9-DiHETrE levels were positively associated with adiponectin levels (r = -0.43, p < 0.05). Conclusion: The present results indicate that the beneficial effects of FO + D on NAFLD may be partially attributed to the impact on gut microbiota and fecal metabolites.

n-3 polyunsaturated fatty acids in phospholipid or triacylglycerol form attenuate nonalcoholic fatty liver disease via mediating cannabinoid receptor 1/adiponectin/ceramide pathway.

n-3 polyunsaturated fatty acids (PUFA) have shown to exert beneficial effects in the treatment of nonalcoholic fatty liver disease (NAFLD). Supplements of n-3 PUFA occur in either phospholipid or triacylglycerol form. The present study aimed to compare whether the different n-3 PUFA of marine-origin, namely krill oil, DHA/EPA-phospholipid (PL), and EPA/DHA-triacylglycerol (TAG) forms had differential abilities to ameliorate NAFLD. The NAFLD model was established in mice fed a high-fat and high-cholesterol diet (HFD). The mice showed evidence of weight gain, dyslipidemia, insulin resistance and hepatic steatosis after 9 weeks of HFD, while the three forms of the n-3 PUFA reduced hepatic TAG accumulation, fatty liver and improved insulin instance, and hepatic biomarkers after 9 weeks of intervention. Of these, krill oil intervention significantly reduced adipocyte hypertrophy and hepatic steatosis in comparison with DHA/EPA-PL and EPA/DHA-TAG groups. Importantly, only krill oil intervention significantly reduced serum alanine transaminase, aspartate transaminase concentrations and low-density lipoprotein-cholesterol, compared with the HFD group. Supplemental n-3 PUFA lowered circulating anandamide (AEA) and 2-arachidonoylglycerol (2-AG) concentrations, compared with the HFD group, which was associated with down-regulating CB1 and upregulating adiponectin expressions in adipose tissue. Besides, targeted lipidomic analyses indicated that the increased adiponectin levels were accompanied by reductions in hepatic ceramide levels. The reduced ceramide levels were associated with inhibiting lipid synthesis and increasing fatty acid ß-oxidation, finally inhibiting TAG accumulation in the liver. Through mediating CB1/adiponectin/ceramide pathway, the present study suggested that administration of krill oil had superior health effects in the therapy of NAFLD in comparison with DHA/EPA-PL and EPA/DHA-TAG.

A meta-analysis of prospective cohort studies of flavonoid subclasses and stroke risk.

Epidemiological studies indicate that higher intakes of flavonoids are associated with reduced stroke risk, however, which subtypes play significant roles to protect against stroke remain unclear. A systematic literature search in PubMed and Web of Science databases was performed up to Oct. 2021. Flavonoids or their subtypes (flavanol, flavanone, flavone, flavan-3-ol, isoflavone, or anthocyanin) were paired with stoke as the search term. Multivariate-adjusted relative risks (RRs) with 95% confidence intervals (CIs) for the highest versus the lowest category were pooled by using a random-effects model. Dose-response analysis was implemented by using a restricted cubic spline regression model. Ten independent prospective cohort studies with 387,076 participants and 9,564 events were included. Higher intakes of flavanones were inversely associated with stroke risk (RR = 0.85; 95%CI: 0.78, 0.93). Dose-response analysis showed that 50 mg/day increment of flavanones was associated with 11% reduction in stroke risk (RR = 0.89; 95%CI: 0.84, 0.94). Flavan-3-ols was marginally inversely associated with stroke risk (RR = 0.92; 95%CI: 0.82, 1.02). Dose-response analysis showed that 200 mg/day increment of flavan-3-ols was associated with 14% reduction in stroke risk (RR = 0.86; 95%CI: 0.75, 0.98). The non-significant association was observed with respect to other flavonoid subclasses. This study demonstrated higher intakes of flavanones and flavan-3-ols were associated with a lower risk of stroke. Dietary intakes of lemon and citrus rich in flavanones and flavan-3-ols might have beneficial functions for the protection against stroke. The findings of these associations of the present study need to be confirmed in other regions and ethnic origins.

The effects of fish oil plus vitamin D3 intervention on non-alcoholic fatty liver disease: a randomized controlled trial.

PURPOSE: The present study aimed to investigate fish oil plus vitamin D3 (FO + D) supplementation on biomarkers of non-alcoholic fatty liver disease (NAFLD). METHODS: In a 3-month randomized controlled trial, 111 subjects with NAFLD, aged 56.0 ± 15.9 y, were randomized into FO + D group (n = 37), fish oil group (FO, n = 37) or corn oil group (CO, n = 37). The subjects consumed the following capsules (3 g/day), which provided 2.34 g/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) + 1680 IU vitamin D3 (FO + D group), or 2.34 g/day of EPA + DHA (FO group), or 1.70 g/d linoleic acid (CO group). RESULTS: Using multivariable-adjusted general linear model, there were significant net reductions in serum alanine aminotransferase (ALT), and triacylglycerol (TAG) and TNF-α levels in the FO + D and FO groups, compared with the control group (P < 0.05). The supplemental FO + D also showed significant reductions in insulin (- 1.58 ± 2.00 mU/L vs. - 0.63 ± 1.55 mU/L, P = 0.050) and IL-1ß (- 6.92 ± 7.29 ng/L vs. 1.06 ± 5.83 ng/L, P < 0.001) in comparison with control group. Although there were no significant differences between FO + D and FO groups regarding biochemical parameters, supplemental FO + D showed decreases in ALT (from 26.2 ± 13.5 U/L to 21.4 ± 9.6 U/L, P = 0.007), aspartate aminotransferase (AST, from 22.5 ± 7.0 U/L to 20.2 ± 4.0 U/L, P = 0.029), HOMA-IR (from 3.69 ± 1.22 to 3.38 ± 1.10, P = 0.047), and TNF-α (from 0.43 ± 0.38 ng/L to 0.25 ± 0.42 ng/L, P < 0.001) levels following the intervention. CONCLUSION: The present study demonstrated that groups supplemented with FO + D and FO had similar beneficial effects on biomarkers of hepatocellular damage and plasma TAG levels in subjects with NAFLD, while in the FO + D group, there were some suggestive additional benefits compared with FO group on insulin levels and inflammation. TRIAL REGISTRATION: ChiCTR1900024866.

N-3 polyunsaturated fatty acids effectively protect against neural tube defects in diabetic mice induced by streptozotocin.

Folate cannot prevent all neural tube defects (NTD), indicating that other pathogeneses still exist except for the folate deficiency. Maternal diabetes mellitus during pregnancy can increase the risk of offspring NTD. Our previous study showed that polyunsaturated fatty acids (PUFA) were lower in the placenta of human NTD cases than in healthy controls, and the supplementation of fish oil (rich in long-chain (LC) n-3 PUFA, mainly C20:5n-3 and C22:6n-3) had a better prevention effect against sodium valproate induced NTD than corn oil (rich in C18:2n-6) and flaxseed oil (rich in C18:3n-3). The aim of the present study was to investigate whether PUFA could prevent diabetes-induced NTD in mice. Streptozotocin (STZ)-induced diabetic pregnant mice were fed with a normal diet (DMC), a diet containing a low dose of fish oil (DMLn-3), a diet containing a high dose of fish oil (DMHn-3) or a diet rich in corn oil (DMn-6). Healthy pregnant mice were fed with a normal diet (HC). Compared with the DMC group, the rate of NTD was significantly lower in the DMHn-3 group (4.44% vs. 12.50%), but not in the DMLn-3 (11.11%) or DMn-6 group (12.03%). The NTD rate in the DMHn-3 group was comparable with that in the HC group (1.33%) (p = 0.246), and lower than that in the DMn-6 group (p = 0.052). The NTD rate in DMLn-3 and DMn-6 groups was significantly higher than that in the HC group. No significant difference was observed in NTD rate between DMLn-3 and DMHn-3 groups, and between DMLn-3 and DMn-6 groups. Compared with the HC group, the DMC group had a significantly lower C22:6n-3 in both serum and embryos. Fish oil supplementation ameliorated neuroepithelial cell apoptosis, and the apoptotic rate was comparable between DMHn-3 and HC groups. Although the apoptotic rate was significantly lower in the DMn-6 group than the DMC group, it was still much higher than that in the HC group. The proteins P53 and Bax in embryos were higher, while the proteins Bcl-2 and Pax3 were lower in the DMC group than in the HC group. The disturbance of Pax3, P53 and Bax induced by diabetes was abolished in DMLn-3, DMHn-3 and DMn-6 groups. Importantly, Bcl-2 in embryos was restored to the normal level only in the DMHn-3 group but not in the DMLn-3 or DMn-6 group. In conclusion, LC n-3 PUFA enriched fish oil has a protective effect against NTD in diabetes induced by STZ through improving neuroepithelial cell apoptosis, and the mechanism may be by increasing the anti-apoptosis protein Bcl-2 independently of Pax3 and P53.

Effects of dietary eicosapentaenoic acid and docosahexaenoic acid supplementation on metabolic syndrome: A systematic review and meta-analysis of data from 33 randomized controlled trials.

BACKGROUND & AIMS: Previous randomized controlled trials (RCTs) have compared the effects of pure preparations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in reducing metabolic syndrome (MetS) risk factors, but the results were inconsistent. The present study aimed to clarify whether EPA and DHA have differential effects on MetS features in humans. METHODS: A systematic literature search was conducted in CNKI, PubMed, Embase and Scopus updated to February 2021. The mean changes in the characteristics of MetS were calculated as weighted mean differences by using a random-effects model. Thirty-three RCTs were included. RESULTS: The results showed that both EPA and DHA were effective at lowering serum triglycerides (TG) levels. EPA supplementation decreased the serum levels of total cholesterol (TC) (WMD = -0.24 mmol/L; 95% CI, -0.43, -0.05 mmol/L), TG (WMD = -0.77 mmol/L; 95% CI, -1.54, -0.00 mmol/L) and low density lipoprotein-cholesterol (LDL-C) (WMD = -0.13 mmol/L; 95% CI, -0.25, -0.01 mmol/L), while DHA increased the serum levels of TC (WMD = 0.14 mmol/L; 95% CI, 0.03, 0.25 mmol/L), LDL-C (WMD = 0.26 mmol/L; 95% CI, 0.15, 0.38 mmol/L) and high density lipoprotein-cholesterol (HDL-C) (WMD = 0.07 mmol/L; 95% CI, 0.04, 0.09 mmol/L). Moreover, DHA increased the serum levels of insulin compared with EPA, especially in subgroups whose mean age was <60 years (0.43 mU/L; 95% CI: 0.04, 0.81 mU/L) and duration of DHA supplementation < 3 months (0.39 mU/L; 95% CI: 0.01, 0.77 mU/L). CONCLUSIONS: The present meta-analysis provides evidence that EPA and DHA have different effects on risk factors of MetS.

Vitamin D and non-alcoholic fatty liver disease: a meta-analysis of randomized controlled trials.

The results of randomized controlled trials (RCTs) investigating supplemental vitamin D on aminotransferases and cardio-metabolic risk factors in subjects with non-alcoholic fatty liver disease (NAFLD) have been inconsistent. The present study aimed to quantitatively evaluate whether supplementation with vitamin D has beneficial effects in treatment of NAFLD. A systematical literature search was performed with Cochrane Library, PubMed, Scopus databases and Web of Science up to June 2020. The mean changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), fasting glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), and triglyceride (TAG) were calculated as standard mean difference (SMD) using a random-effects model. Pre-specified subgroup and univariate meta-regression analyses were performed to identify the sources of heterogeneity. Ten trials with a total of 544 NAFLD subjects were included for data synthesis. The summary estimates indicated that supplemental vitamin D significantly reduced the levels of serum/plasma fasting glucose (-0.22; 95%CI: -0.39, -0.04), insulin (-0.68; 95%CI: -1.22, -0.14) and HOMA-IR (-1.32; 95%CI: -2.30, -0.34), and marginally reduced the ALT (-0.18; 95%CI: -0.39, 0.04) and TAG (-10.38; 95%CI: -21.09, 0.34) levels. However, the pooled effect did not support that supplemental vitamin D was beneficial for concentrations of AST, TC, HDL-C and LDL-C. The present study provides substantial evidence that supplemental vitamin D has favorable effects on glycemic control and insulin sensitivity in NAFLD patients. Vitamin D could be as an adjuvant pharmacotherapy of NAFLD.

Pure omega 3 polyunsaturated fatty acids (EPA, DPA or DHA) are associated with increased plasma levels of 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) in a short-term study in women.

3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is a metabolite of furan fatty acids found in plasma and urine of humans after consumption of foods containing these fatty acids. Recently, CMPF has been identified as a prominent metabolite following the consumption of either fish oil, fish oil fatty acid-ethyl esters or diets rich in fish. As furan fatty acids are known to occur in fish and fish oils (at a low level), it is possible that in these studies the CMPF in plasma originated from furan fatty acids. We report the plasma CMPF levels in 10 healthy women who consumed 1 gram of pure eicosapentaenoic acid (EPA), or docosapentaenoic acid (DPA) or docosahexaenoic acid (DHA), or olive oil daily for 6 days, in a cross-over study. The supplemented omega 3 fatty acids contained no detectable levels of furan fatty acids. The plasma CMPF and omega 3 fatty acid levels were measured by LC-MS/MS. Consumption of pure omega 3 fatty acids led to a significant increase in the plasma CMPF levels, but not with olive oil (from 1.6 to 2.5-fold compared with baseline). The plasma free fatty acid levels of EPA, DPA and DHA also increased significantly when they were supplemented (p < 0.05). Significant positive correlations existed between the plasma free fatty acid DPA and DHA levels (p < 0.05 and r = +0.49 to +0.81), but not between the EPA and CMPF levels. These data suggest that purified long chain omega 3 fatty acids may be precursors of CMPF; however the metabolic pathway(s) from omega 3 fatty acids to CMPF remain to be elucidated.

Different metabolism of EPA, DPA and DHA in humans: A double-blind cross-over study.

This study aimed to compare eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) incorporated into red blood cells (RBC) phospholipids (PL), plasma PL, plasma triglyceride (TAG), and plasma cholesteryl ester (CE) fractions, and the metabolomics profiles in a double-blind cross-over study. Twelve female healthy subjects randomly consumed 1 g per day for 6 days of pure EPA, DPA, or DHA. The placebo treatment was olive oil. The fasting venous blood was taken at days 0, 3 and 6, and the RBC PL and plasma lipid fractions were separated for fatty acid determination using thin layer chromatography followed by gas chromatography. Plasma metabolites were analyzed by UHPLC-Q-Exactive Orbitrap/MS. Supplemental EPA significantly increased the concentrations of EPA in RBC PL (days 3 and 6). For subjects consuming the DPA supplement, the concentrations of both DPA and EPA were significantly increased in RBC PL over a 6-day period, respectively. For plasma PL fraction, EPA and DPA supplementation significantly increased the concentrations of EPA and DPA at both days 3 and 6, respectively. Supplemental DHA significantly increased the concentrations of DHA in plasma PL at day 6. For plasma TAG fraction, supplementation with EPA and DPA significantly increased the concentrations of EPA and DPA at both days 3 and 6, respectively. After DHA supplementation, significant increases in the concentrations of DHA were found relative to baseline at both days 3 and 6. For plasma CE fraction, EPA supplementation significantly increased the concentrations of EPA (days 3 and 6) and DPA (days 6), respectively. Supplemental DPA significantly increased the concentrations of EPA at day 6. Meanwhile, the concentrations of DHA were significantly increased over a 6-day period of intervention after subjects consuming the DHA supplements. There were a total of 922 plasma metabolites identified using metabolomics analyses. Supplementation with DPA and DHA significantly increased the levels of sphingosine 1-phosphate (P for DPA = 0.025, P for DHA = 0.029) and 15-deoxy-Δ12,14-prostaglandin A1 (P for DPA = 0.034; P for DHA = 0.021) in comparison with olive oil group. Additionally, supplementation with EPA (P = 0.007) and DHA (P = 0.005) significantly reduced the levels of linoleyl carnitine, compared with olive oil group. This study shows that DPA might act as a reservoir of n-3 LCP incorporated into blood lipid fractions, metabolized into DHA, and retro-converted back to EPA. Metabolomics analyses indicate that supplemental EPA, DPA and DHA have shared and differentiated metabolites. The differences of these metabolic biomarkers should be investigated in additional studies.

Effect of Betaine on Reducing Body Fat-A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Animal studies have shown the beneficial effect of betaine supplementation on reducing body fat, while the data from human studies are controversial and inconsistent. The objective of the present systematic review was to investigate the effects of betaine intervention on treating obesity in humans and quantitatively evaluate the pooled effects based on randomized controlled trials with a meta-analysis. The PubMed and Scopus databases, and the Cochrane Library, were searched up to September 2019. Weighted mean differences were calculated for net changes in obesity-related indices by using a random-effects model. Publication bias was estimated using Begg's test. Six studies with 195 participants were identified. Betaine supplementation significantly reduced the total body fat mass (-2.53 kg; 95% CI: -3.93, -0.54 kg; I2 = 6.6%, P = 0.36) and body fat percentage (-2.44%; 95% CI: -4.20, -0.68%; I2 = 0.0%, P = 0.44). No changes were observed regarding body weight (-0.29 kg; 95% CI: -1.48, 0.89 kg; I2 = 0.00%, P = 0.99) and body mass index (-0.10 kg/m2; 95% CI: -5.13, 0.31 kg/m2; I2 = 0.00%, P = 0.84). The results suggested that dietary betaine supplementation might be an effective approach for reducing body fat.

Effects of EPA and DHA on blood pressure and inflammatory factors: a meta-analysis of randomized controlled trials.

The present study aimed to clarify whether eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have differential effects on blood pressure and inflammatory mediators. A systematic literature search was conducted in PubMed and Scopus updated to Apr. 2018. The mean changes in risk factors of chronic diseases were calculated as weighted mean difference (WMD) by using a random-effects model. Twenty randomized controlled trials (RCTs) were included. The summary estimate showed that EPA intervention significantly reduced systolic blood pressure (SBP) (-2.6 mmHg; 95%confident interval (CI): -4.6, -0.5 mmHg), especially in subjects with dyslipidemia (-3.8 mmHg; 95%CI: -6.7, -0.8 mmHg). The pooled effect indicated that supplemental DHA exerted a significant reduction in diastolic blood pressure (DBP) in subjects with dyslipidemia (-3.1 mmHg; 95%CI: -5.9, -0.2 mmHg). Both EPA (-0.56 mg/L; 95%CI: -1.13, 0.00) and DHA (-0.5 mg/L; 95%CI: -1.0, -0.03) significantly reduced the concentrations of C-reactive protein (CRP), respectively, especially in subjects with dyslipidemia and higher baseline CRP concentrations. Given that limited trials have focused on EPA or DHA intervention on concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α, further RCTs should be explored on these inflammatory factors. The present meta-analysis provides substantial evidence that EPA and DHA have independent (blood pressure) and shared (CRP concentration) effects on risk factors of chronic diseases, and high-quality RCTs with multi-center and large simple-size should be performed to confirm the present findings.

Effects of resveratrol supplementation on risk factors of non-communicable diseases: A meta-analysis of randomized controlled trials.

The results of randomized controlled trials (RCTs) investigating resveratrol supplementation on risk factors of non-communicable diseases (NCDs) have been inconsistent. The present meta-analysis aimed to quantitatively evaluate the effects of resveratrol intervention on risk factors of NCDs. PubMed and Scopus databases were searched up to June 2017. Weighted mean differences were calculated for net changes in risk factors of NCDs by using a random-effects model. Pre-specified subgroup and univariate meta-regression analyses were carried out to explore the sources of heterogeneity. Twenty-nine studies (30 treatment arms) with 1069 participants were identified. Resveratrol supplementation significantly reduced the concentrations of fasting glucose (-4.77 mg/dL; 95% CI: -9.33 to -0.21 mg/dL; P = 0.040), total cholesterol (TC) (-9.75 mg/dL; 95% CI: -17.04 to -2.46 mg/dL; P = 0.009), and C-reactive protein (CRP) (-0.81 mg/L; 95% CI: -1.42 to -0.21 mg/L; P = 0.009). Resveratrol intervention exerted significant reductions in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in subjects with type 2 diabetes mellitus (T2DM). Subgroup analysis also showed that the trials with resveratrol intervention ≥3 months significantly reduced the low-density lipoprotein cholesterol (LDL-C), DBP, and glycated hemoglobin (HbA1c) values. The results did not support that resveratrol intervention had favorable effects in altering high-density lipoprotein cholesterol (HDL-C), triglyceride (TAG), and homeostasis model assessment of insulin resistance (HOMA-IR). The present study provides substantial evidence that resveratrol supplementation has favorable effects on several risk factors of NCDs.

Differential effects of EPA, DPA and DHA on cardio-metabolic risk factors in high-fat diet fed mice.

The aim of the present study was to assess and compare the effects of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) supplementation on lipid metabolism in 4 month-old male C57BL/6J mice fed a high-fat diet. The high-fat fed mice showed evidence of fatty liver, obesity and insulin resistance after being on the high-fat diet for 6 weeks compared with the control low-fat diet fed mice. Supplementation of the high-fat diet with either EPA, DPA or DHA prevented the fatty liver, prevented high serum cholesterol and serum glucose and prevented high liver cholesterol levels. DPA (but not EPA or DHA) was associated with a significantly improved homeostasis model assessment of insulin resistance (HOMA-IR) compared with the high-fat fed mice. Supplementation with DPA and DHA both prevented the decreased serum adiponectin levels, compared with EPA and the high-fat diet. In addition, supplementation with DPA and DHA both prevented the increased serum alanine aminotransferase (ALT) levels compared with EPA and the high-fat group, which can be attributed to down-regulation of TLR-4/NF-κB signaling pathway and decreasing lipogenesis in the liver. Therefore, DPA and DHA seem to exert similar effects in cardio-metabolic protection against the high-fat diet and these effects seem to be different to those of EPA.

Fatty acid and non-alcoholic fatty liver disease: Meta-analyses of case-control and randomized controlled trials.

BACKGROUND AND AIMS: Blood and/or liver fatty acid contents of healthy subjects and non-alcoholic fatty liver disease (NAFLD) patients have shown inconsistent associations. In addition, the results of randomized controlled trials (RCTs) in relation to the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on alanine aminotransferase (ALT), aspartate aminotransferase (AST), liver fat, triglyceride (TAG) and fasting glucose levels are inconsistent. The present study aimed to investigate the differences of fatty acid content in the blood and/or liver tissue between healthy subjects and NAFLD patients, and to quantify the benefits of n-3 PUFA therapy in NAFLD patients. METHODS: A systematic literature search was performed up to November 2016 using PubMed and Scopus databases. The differences of fatty acid content between cases and controls were calculated as weighted mean differences (WMD) by using a random-effects model. The intervention effects of RCTs were calculated as WMD for net changes in ALT, AST, liver fat, TAG and fasting glucose levels, respectively. Meta-regression with restricted maximum likelihood estimation was used to evaluate a potential linear relationship between confounding factors and effect sizes. Generalized least square was performed for dose-response analysis. RESULTS: Ten eligible case-control studies and 11 RCTs were included. The pooled estimates of case-control studies showed that blood and/or liver docosahexaenoic acid (DHA) content was significantly higher in the controls compared with cases. The pooled estimates of RCTs showed that n-3 PUFA supplementation significantly reduced the ALT (-7.53 U/L; 95% CI: -9.98, -5.08 U/L), ASL (-7.10 U/L, 95% CI: -11.67, -2.52 U/L) and TAG (-36.16 mg/dL, 95% CI: -49.15, -23.18 mg/dL) concentrations, and marginally reduced the liver fat content (-5.11%, 95% CI: -10.24, 0.02%, P = 0.051), but not fasting glucose. Dose-response analysis of RCTs showed that 1 g per day increment of eicosapentaenoic acid (EPA)+DHA was associated with a 3.14 U/L, 2.43 U/L, 2.74% and 9.97 mg/dL reduction in ALT (95% CI: -5.25, -1.02 U/L), AST (95% CI: -3.90, -0.90 U/L), liver fat (95% CI: -4.32, -1.16%) and TAG (95% CI: -14.47, -5.48 mg/dL) levels, respectively. CONCLUSIONS: The present meta-analysis provides substantial evidence that n-3 PUFA supplementation, especially DHA, has a favorable effect in treatment of NAFLD.

fat-1 mice prevent high-fat plus high-sugar diet-induced non-alcoholic fatty liver disease.

High-fat and high-sugar (HFS) diets have been suggested to play a causal role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate whether fat-1 transgenic mice with a higher tissue content of n-3 polyunsaturated fatty acids (PUFAs) could prevent HFS diet-induced NAFLD, compared with wild-type mice. The fat-1 and wild-type littermates had free access to a 15% fructose solution plus high-fat diet, a 15% glucose solution plus high-fat diet, or a 15% sucrose solution plus high-fat diet, respectively. Caloric intake, weight gain, biochemical parameters, histology, and gene and protein expression levels were measured after 8 weeks of intervention. Liquid intake in glucose- or sucrose-fed mice was about 2-fold compared with that in fructose-fed mice. The wild-type mice given glucose showed the highest total caloric intake and weight gain compared to the other groups. The serum concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and alanine transaminase (ALT) were significantly lowered in fat-1 groups compared with their paired wild-type groups. Histological analysis showed that the wild-type groups fed the HFS diets developed hepatic lipid accumulation and steatosis, compared with the fat-1 groups. The gene and protein expression levels involved in fatty acid synthesis and the toll-like receptor (TLR)-4 signaling pathway were significantly inhibited in the fat-1 groups compared with the wild-type groups. The endogenously synthesized n-3 PUFAs of the three fat-1 groups, which inhibit fatty acid synthesis and the TLR-4 signaling pathway, prevent HFS diet-induced NAFLD.

n-3 Polyunsaturated Fatty Acids and Metabolic Syndrome Risk: A Meta-Analysis.

The associations between n-3 polyunsaturated fatty acids (PUFAs) and metabolic syndrome (MetS) risk have demonstrated inconsistent results. The present study aimed to investigate whether higher circulating n-3 PUFAs and dietary n-3 PUFAs intake have a protective effect on MetS risk. A systematic literature search in the PubMed, Scopus, and Chinese National Knowledge Infrastructure (CNKI) databases was conducted up to March 2017. Odd ratios (ORs) from case-control and cross-sectional studies were combined using a random-effects model for the highest versus lowest category. The differences of n-3 PUFAs between healthy subjects and patients with MetS were calculated as weighted mean difference (WMD) by using a random-effects model. Seven case-control and 20 cross-sectional studies were included. A higher plasma/serum n-3 PUFAs was associated with a lower MetS risk (Pooled OR = 0.63, 95% CI: 0.49, 0.81). The plasma/serum n-3 PUFAs in controls was significantly higher than cases (WMD: 0.24; 95% CI: 0.04, 0.43), especially docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA). However, no significant association was found between dietary intake of n-3 PUFAs or fish and MetS risk. The present study provides substantial evidence of a higher circulating n-3 PUFAs associated with a lower MetS risk. The circulating n-3 PUFAs can be regarded as biomarkers indicating MetS risk, especially DPA and DHA.

The effects of Lycium barbarum L. (L. barbarum) on cardiometabolic risk factors: a meta-analysis of randomized controlled trials.

The effects of Lycium barbarum L. (L. barbarum) on the cardiometabolic risk factors from randomized controlled trials (RCTs) have shown inconsistent results. The present meta-analysis aimed to investigate the effects of L. barbarum supplementation on the cardiometabolic risk factors. A systematic literature search was performed in Chinese National Knowledge Infrastructure (CNKI), PubMed, Scopus, and Wanfang databases updated to March 2017. The mean changes in cardiometabolic risk factors were calculated as the weighted mean difference (WMD) using a random-effects model. Seven RCTs with a total of 548 subjects were included. The pooled estimate showed that L. barbarum intervention significantly reduced the fasting glucose concentrations (-0.36 mmol L-1/-6.5 mg dL-1; 95% confident interval (CI): -0.62, -0.10 mmol L-1/-11.3, -1.8 mg dL-1). In addition, L. barbarum supplementation marginally reduced the concentrations of total cholesterol (TC) (-0.30 mmol L-1/-11.6 mg dL-1; 95% CI: -0.75, 0.15 mmol L-1/-29.0, 5.8 mg dL-1; P = 0.189) and triglyceride (TG) (-0.20 mmol L-1/-17.7 mg dL-1; 95% CI: -0.46, 0.05 mmol L-1/-40.7, 4.4 mg dL-1; P = 0.122), but the summary estimates did not reach statistical significance. No benefit was found in relation to bodyweight and blood pressure. The present meta-analysis provides some evidence that supplemental L. barbarum might have favourable effect on glucose control.