Validation of Nutritional Approaches to Modulate Cardiovascular and Diabetic Risk Factors in Patients with Hypertriglyceridemia or Prediabetes-The MoKaRi II Randomized Controlled Study.

Hypertriglyceridemia and diabetes mellitus type 2 are among the most important metabolic diseases globally. Diet plays a vital role in the development and progression of both clinical pictures. For the 10-week randomized, controlled, intervention study, 67 subjects with elevated plasma triglyceride (TG) concentrations (≥1.7 mmol/L) and 69 subjects with elevated fasting glucose concentrations (≥5.6 < 7.0 mmol/L) were recruited. The intervention groups received specially developed, individualized menu plans and regular counseling sessions to lower (A) TG or (B) fasting glucose and glycated hemoglobin A1c as well as other cardiovascular and diabetic risk factors. The hypertriglyceridemia intervention group was further supplemented with fish oil (3.5 g/d eicosapentaenoic acid + docosahexaenoic acid). The two control groups maintained a typical Western diet. Blood samples were taken every 2 weeks, and anthropometric data were collected. A follow-up examination was conducted after another 10 weeks. In both intervention groups, there were comparable significant reductions in blood lipids, glucose metabolism, and anthropometric parameters. These results were, with a few exceptions, significantly more pronounced in the intervention groups than in the corresponding control groups (comparison of percentage change from baseline). In particular, body weight was reduced by 7.4% (6.4 kg) and 7.5% (5.9 kg), low-density lipoprotein cholesterol concentrations by 19.8% (0.8 mmol/L) and 13.0% (0.5 mmol/L), TG concentrations by 18.2% (0.3 mmol/L) and 13.0% (0.2 mmol/L), and homeostatic model assessment for insulin resistance by 31.8% (1.1) and 26.4% (0.9) (p < 0.05) in the hypertriglyceridemia and prediabetes intervention groups, respectively. Some of these changes were maintained until follow-up. In patients with elevated TG or fasting glucose, implementing individualized menu plans in combination with regular counseling sessions over 10 weeks led to a significant improvement in cardiovascular and diabetic risk factors.

An abundant biliary metabolite derived from dietary omega-3 polyunsaturated fatty acids regulates triglycerides.

Omega-3 fatty acids from fish oil reduce triglyceride levels in mammals, yet the mechanisms underlying this effect have not been fully clarified, despite the clinical use of omega-3 ethyl esters to treat severe hypertriglyceridemia and reduce cardiovascular disease risk in humans. Here, we identified in bile a class of hypotriglyceridemic omega-3 fatty acid-derived N-acyl taurines (NATs) that, after dietary omega-3 fatty acid supplementation, increased to concentrations similar to those of steroidal bile acids. The biliary docosahexaenoic acid-containing (DHA-containing) NAT C22:6 NAT was increased in human and mouse plasma after dietary omega-3 fatty acid supplementation and potently inhibited intestinal triacylglycerol hydrolysis and lipid absorption. Supporting this observation, genetic elevation of endogenous NAT levels in mice impaired lipid absorption, whereas selective augmentation of C22:6 NAT levels protected against hypertriglyceridemia and fatty liver. When administered pharmacologically, C22:6 NAT accumulated in bile and reduced high-fat diet-induced, but not sucrose-induced, hepatic lipid accumulation in mice, suggesting that C22:6 NAT is a negative feedback mediator that limits excess intestinal lipid absorption. Thus, biliary omega-3 NATs may contribute to the hypotriglyceridemic mechanism of action of fish oil and could influence the design of more potent omega-3 fatty acid-based therapeutics.

DGAT1 mutations leading to delayed chronic diarrhoea: a case report.

BACKGROUND: Early-onset chronic diarrhoea often indicates a congenital disorder. Mutation in diacylglycerol o-acyltransferase 1 (DGAT1) has recently been linked to early-onset chronic diarrhoea. To date, only a few cases of DGAT1 deficiency have been reported. Diarrhoea in those cases was severe and developed in the neonatal period or within 2 months after birth. CASE PRESENTATION: Here, we report a female patient with DGAT1 mutations with delayed-onset chronic diarrhoea. The patient had vomiting, hypoalbuminemia, hypertriglyceridemia, and failure to thrive at early infancy. Her intractable chronic diarrhoea occurred until she was 8 months of age. A compound heterozygous DGAT1 mutation was found in the patient, which was first found in the Chinese population. Her symptoms and nutrition status improved after nutritional therapy, including a fat restriction diet. CONCLUSIONS: This case expanded our knowledge of the clinical features of patients with DGAT1 mutations. Intractable diarrhoea with delayed onset could also be a congenital disorder.

Effect of intermittent versus continuous calorie restriction on body weight and cardiometabolic risk markers in subjects with overweight or obesity and mild-to-moderate hypertriglyceridemia: a randomized trial.

BACKGROUND: Intermittent calorie restriction (ICR) is a novel method of dietary restriction for body weight control with the potential to improve obesity-related cardiometabolic markers, but the impact of this diet on subjects with hypertriglyceridemia (HTG) remains unknown. METHODS: Eighty-eight subjects with overweight or obesity and mild-to-moderate HTG were randomized to the continuous calorie restriction (CCR) group, or ICR group (a very low-calorie diet during 3 days of the week) for 8 weeks (44 patients in each group). Body composition, plasma lipids, glucose, insulin, adiponectin, and liver enzymes were measured at baseline and after 8 weeks. An intention-to-treat analysis was performed. RESULTS: The body weight decreased in both groups (4.07 ± 1.83 kg in the CCR group and 4.57 ± 2.21 kg in the ICR group) with no significant difference between the groups. There was no significant difference between the two groups in the reduced amount of fat mass, fat-free mass, and waist circumference. Both groups achieved a significant reduction in plasma triglycerides after 8 weeks (by 15.6 and 6.3% in ICR and CCR groups, respectively) with no difference between treatment groups. HOMA-IR improved significantly in ICR compared to the CCR group (P = 0.03). Plasma glucose, insulin, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, liver enzyme, and adiponectin were not different between the two groups. CONCLUSIONS: The results of this short-term study suggest that three-days a week of the ICR is comparable to a CCR diet for the reduction of triglycerides level in patients with HTG and in the short-term it appears to be more effective than continuous dieting in improving insulin resistance. However, longer-term studies are needed to confirm these findings. TRIAL REGISTRATION: Trial registration number: NCT04143971 .

Reversal of severe hypertriglyceridemia with intermittent fasting and a very-low-carbohydrate ketogenic diet: a case series.

PURPOSE OF REVIEW: To illustrate successful reversal of hypertriglyceridemia using a very-low-carbohydrate ketogenic diet in conjunction with intermittent fasting in two patients. RECENT FINDINGS: Hypertriglyceridemia remains an important component of residual risk for atherosclerotic cardiovascular disease. Current guidelines from the AHA/ACC recommend the initiation of a very-low-fat diet to treat persistently elevated triglycerides, whereas the National Lipid Association argues that a very-low-carbohydrate, high-fat diet is contraindicated in severe hypertriglyceridemia. In contrast, we report resolution of two cases of severe hypertriglyceridemia with implementation of very-low-carbohydrate ketogenic diets and intermittent fasting. SUMMARY: Here, we describe two patients who have demonstrated substantial reductions in serum triglycerides, effectively reversing severe hypertriglyceridemia using unconventional dietary methods. Although anecdotal, these cases point to a critical lack of flexibility in current dietary guidelines that hinder their application in clinical practice.

Omega-3 fatty acid exposure with a low-fat diet in patients with past hypertriglyceridemia-induced acute pancreatitis; an exploratory, randomized, open-label crossover study.

BACKGROUND: Omega-3 fatty acids (OM3-FAs) are recommended with a low-fat diet for severe hypertriglyceridemia (SHTG), to reduce triglycerides and acute pancreatitis (AP) risk. A low-fat diet may reduce pancreatic lipase secretion, which is required to absorb OM3-ethyl esters (OM3-EEs), but not OM3-carboxylic acids (OM3-CAs). METHODS: In this exploratory, randomized, open-label, crossover study, 15 patients with SHTG and previous AP were instructed to take OM3-CA (2 g or 4 g) and OM3-EE 4 g once daily for 4 weeks, while adhering to a low-fat diet. On day 28 of each treatment phase, a single dose was administered in the clinic with a liquid low-fat meal, to assess 24-h plasma exposure. Geometric least-squares mean ratios were used for between-treatment comparisons of baseline (day 0)-adjusted area under the plasma concentration versus time curves (AUC0-24) and maximum plasma concentrations (Cmax) for eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). RESULTS: Before initiating OM3-FA treatment, mean baseline fasting plasma EPA + DHA concentrations (nmol/mL) were 723 for OM3-CA 2 g, 465 for OM3-CA 4 g and 522 for OM3-EE 4 g. At week 4, mean pre-dose fasting plasma EPA + DHA concentrations increased by similar amounts (+ 735 - + 768 nmol/mL) for each treatment. During the 24-h exposure assessment (day 28), mean plasma EPA + DHA increased from pre-dose to the maximum achieved concentration by + 32.7%, + 45.8% and + 3.1% with single doses of OM3-CA 2 g, OM3-CA 4 g and OM3-EE 4 g, respectively. Baseline-adjusted AUC0-24 was 60% higher for OM3-CA 4 g than for OM3-EE 4 g and baseline-adjusted Cmax was 94% higher (both non-significant). CONCLUSIONS: Greater 24-h exposure of OM3-CA versus OM3-EE was observed for some parameters when administered with a low-fat meal at the clinic on day 28. However, increases in pre-dose fasting plasma EPA + DHA over the preceding 4-week dosing period were similar between treatments, leading overall to non-significant differences in baseline (day 0)-adjusted AUC0-24 and Cmax EPA + DHA values. It is not clear why the greater 24-h exposure of OM3-CA versus OM3-EE observed with a low-fat meal did not translate into significantly higher pre-dose fasting levels of DHA + EPA with longer-term use. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02189252, Registered 23 June 2014.

Sciadonic acid derived from pine nuts as a food component to reduce plasma triglycerides by inhibiting the rat hepatic Δ9-desaturase.

Sciadonic acid (Scia) is a Δ5-olefinic fatty acid that is particularly abundant in edible pine seeds and that exhibits an unusual polymethylene-interrupted structure. Earlier studies suggested that Scia inhibited the in vitro expression and activity of the Stearoyl-CoA Desaturase 1 (SCD1), the hepatic Δ9-desaturase involved in the formation of mono-unsaturated fatty acids. To confirm this hypothesis, rats were given 10% Scia in diets balanced out with n-6 and n-3 fatty acids. In those animals receiving the Scia supplement, monoene synthesis in the liver was reduced, which was partly attributed to the inhibition of SCD1 expression. As a consequence, the presence of Scia induced a 50% decrease in triglycerides in blood plasma due to a reduced level of VLDL-secreted triglycerides from the liver. In non-fasting conditions, results showed that Scia-induced inhibition of SCD1 led to a decrease in the proportions of 16:1n-7 and 18:1n-7 in the liver without impacting on the level of 18:1n-9, suggesting that only triglycerides with neosynthesized monoenes are marked out for release. In conclusion, this in vivo study confirms that Scia highly inhibits SCD1 expression and activity. The work was performed on normo-triglyceride rats over six weeks, suggesting promising effects on hyper-triglyceridemic models.

Eruptive xanthomas in a patient with soft-drink diabetic ketosis and apolipoprotein E4/2.

Soft-drink diabetic ketosis, characterized by acute onset ketosis induced by excessive ingestion of sugar-containing drinks, is often seen in obese, young patients, even with undiagnosed type 2 diabetes. We herein report a 15-year-old obese patient with the apolipoprotein E4/2 phenotype, in whom eruptive xanthomas lead to a diagnosis of soft-drink diabetic ketosis. He developed multiple asymptomatic yellowish papules on the auricles, back, buttocks and the extensor surfaces of the elbows and knees. He initially visited a dermatology clinic and his blood triglyceride and HbA1c levels were found to be 6,490 mg/dL and 16.5%, respectively. He was referred to our hospital for treatment of hyperglycemia and hypertyriglyceridemia. On admission, he had ketonuria and increased blood levels of 3-hydroxybutylate and acetoacetate. He habitually drank 1-3 litters of sweet beverages daily to quench his thirst. Therefore, "soft-drink diabetic ketosis" was diagnosed. Severe hypertriglyceridemia was considered to have been a consequence of impaired insulin action and his apolipoprotein E4/2 phenotype. We treated the diabetic ketosis and hypertriglyceridemia with intensive insulin therapy and a fat-restricted diet. At discharge, he no longer required insulin therapy and his blood glucose levels were controlled with metformin and voglibose. Along with amelioration of the hyperglycemia, triglyceride levels decreased to 247 mg/dL without administration of anti-hyperlipidemia agents. The eruptive xanthoma lesions gradually diminished in size and number and eventually disappeared by 12 months. This case provides an instructive example of eruptive xanthomas serving as a sign of severe dysregulation, not only of lipid, but also glucose, metabolism.

Effect of omega-3 fatty acids supplementation combined with lifestyle intervention on adipokines and biomarkers of endothelial dysfunction in obese adolescents with hypertriglyceridemia.

Obesity in adolescents is considered a major public health problem; combined interventional approaches such as omega-3 supplementation with lifestyle intervention (LI) might exert synergistic effects and exceed the impact of each individual strategy. The purpose of the present study was to evaluate if the supplementation of omega-3 with LI could improve metabolic and endothelial abnormality in obese adolescents with hypertriglyceridemia. The study involved sixty-nine adolescents with normal weight and seventy obese adolescents with hypertriglyceridemia. All obese adolescents were applied to LI and randomly assigned to omega-3 supplementation or placebo group for 12 weeks. The obese adolescents with hypertriglyceridemia presented increased levels of leptin, retinol binding protein 4 (RBP4), selectin E (sE) and asymmetric dimethylarginine (ADMA) and decreased levels of adiponectin compared with control subjects. After 12-week intervention, omega-3 supplementation with LI decreased significantly in triglycerides, HOMA, leptin, RBP4, ADMA and sE. Moreover, omega-3 with LI displayed a significant reduction in triglycerides, ADMA and sE in comparison with LI alone. In subjects with omega-3 combined with LI assessed by multivariate regression model, the reduction in triglycerides was the only independent determinant of the decrease in ADMA. The reductions in triglycerides and HOMA were significantly contributed to the changes in sE. Our data indicated that omega-3 combined with LI in short duration significantly improved dyslipidemia, insulin resistance, abnormality of adipokines, endothelial dysfunction in comparison of LI alone, indicating the combined approach is an effective clinical and applicable strategy to control metabolic abnormality and decrease the risks of cardiovascular diseases in obese adolescents.

Hypertriglyceridemia in statin-treated US adults: the National Health and Nutrition Examination Survey.

BACKGROUND: Statin therapy remains the primary treatment for mixed dyslipidemia, even with moderate triglyceride (TG) elevations. OBJECTIVE: We examined the prevalence of elevated TG levels in adults with and without statin use and the associated 10-year predicted atherosclerotic cardiovascular disease (ASCVD) risk. METHODS: We studied 9593 US adults aged ≥20 years (219.9 million projected) in the US National Health and Nutrition Examination Surveys, 2007 to 2014. We determined the proportions of TG categories (<150, 150-199, 200-499, and ≥500 mg/dL) according to statin use, as well as the 10-year estimated ASCVD risk and number of events. RESULTS: Among those not taking statin therapy, the prevalence of TG < 150, 150 to 199, and ≥200 mg/dL was 75.3%, 12.8%, and 11.9%; among statin users, these proportions were 68.4%, 16.2%, and 15.4%, respectively. Among persons with low-density lipoprotein cholesterol <100 mg/dL (or <70 mg/dL in those with ASCVD), despite statin use, 27.7% had TG ≥ 150 mg/dL. The odds of TG ≥ 150 mg/dL in statin users was associated with greater age, higher body mass index, lower high-density lipoprotein cholesterol, higher low-density lipoprotein cholesterol, and diabetes. Estimated mean 10-year ASCVD risk from TG < 150 to ≥500 mg/dL, ranged from 11.3% to 19.1% in statin users and 6.0% to 15.6% in nonusers, with an overall 3.4 million ASCVD events expected in the next 10 years. CONCLUSIONS: One-fourth of US adults overall, including nearly one-third of those on statin therapy, have suboptimal TG levels. More than 3 million ASCVD events are expected to occur over the next decade in those with TG ≥ 150 mg/dL, with approximately 1 million events expected in statin users.

A low-fat spread with added plant sterols and fish omega-3 fatty acids lowers serum triglyceride and LDL-cholesterol concentrations in individuals with modest hypercholesterolaemia and hypertriglyceridaemia.

PURPOSE: The primary and secondary objectives were to investigate the triglyceride (TG) and LDL-cholesterol (LDL-C) lowering effects of a spread with added plant sterols (PS) and fish oil as compared to a placebo spread. METHODS: This study had a randomized, double-blind, placebo-controlled, parallel group design with two intervention arms. Following a 2-week placebo run-in period, 260 healthy individuals with modestly elevated blood TG (≥ 1.4 mmol/L) and LDL-C (≥ 3.4 mmol/L) concentrations consumed either the placebo or intervention spread for 4 weeks. The intervention spread contained 2.0 g/day PS and 1.0 g/day eicosapentaenoic acid (EPA) + docosahexanoic acid (DHA) from fish oil. Fasting serum lipids and apolipoproteins (Apo) (exploratory) were measured at the end of the run-in and intervention phases. RESULTS: Four-week consumption of the intervention spread resulted in significantly lower TG (- 10.6%, 95% CI - 16.0 to - 4.9%; P < 0.001) and LDL-C concentrations (- 5.2%; 95% CI - 7.8 to - 2.4%) as compared to placebo. Total cholesterol (- 3.9%; 95% CI - 6.1 to - 1.5%), non-HDL-C (- 5.4%; 95% CI - 8.1 to - 2.7%), remnant-cholesterol (- 8.1%; 95% CI - 3.4 to - 12.5%), ApoAII (- 2.9%; 95% CI - 5.5 to - 0.2%), ApoCIII (- 7.7%; 95% CI - 12.1 to - 3.1%) and ApoB (- 3.2%; 95% CI - 5.9 to - 0.4%) concentrations were also significantly lower, as compared to placebo. No significant treatment effects were found for HDL-cholesterol, ApoAI, ApoCII, Apo E or ApoB/ApoAI. CONCLUSIONS: Four-week consumption of the intervention spread led to significant and clinically relevant decreases in serum TG, LDL-C and other blood lipid concentrations. The study was registered at clinicaltrials.gov (NCT02728583).

The Effects of Long-Term Dietary Therapy on Patients with Hypertriglyceridemia.

AIM: This study aimed to evaluate the effect of diet on serum lipids and to assess the effectiveness of long-term dietary therapy for hypertriglyceridemia. METHODS: Seventy-nine patients (34 males and 45 females) with hypertriglyceridemia were enrolled and underwent dietary counseling for 12 months based on the following three recommendations: (1) reduce carbohydrate intake, (2) increase n-3 polyunsaturated fatty acid (PUFA) intake, and (3) limit alcohol drinking. We examined the effect of dietary therapy for 6 months on serum triglyceride (TG) levels and also compared the effectiveness of dietary and combined drug therapies on preventing arteriosclerotic disease from 7 to 12 months. RESULTS: We observed that serum TG levels of the patients receiving dietary counseling were decreased compared with baseline at 6 months. Body weight and serum TG levels were decreased, and serum high-density lipoprotein levels were increased in the dietary therapy alone group, whereas BW, body mass index, and abdominal circumference were decreased in the combined drug treatment group compared with baselines at 6 and 12 months. Furthermore, the dietary therapy alone group demonstrated reductions in intake of total energy, carbohydrate, and saturated fatty acids, as well as n-6/n-3 PUFA ratio compared with baselines, but only n-6/n-3 PUFA ratio was decreased in the combined drug treatment group. CONCLUSION: This study demonstrated a decrease in serum TG level after 12 months of dietary therapy similar to drug therapy, which suggests that it is an effective treatment for hypertriglyceridemia, and heightened awareness should be made to encourage its use.The clinical trial registration number: UMIN000028860.

Perilla Oil Supplementation Improves Hypertriglyceridemia and Gut Dysbiosis in Diabetic KKAy Mice.

SCOPE: The aim of this study is to examine whether perilla oil supplementation improves glucolipid metabolism and modulates gut microbiota in diabetic KKAy mice. METHODS AND RESULTS: The successfully established diabetic KKAy mice are randomized into four groups: diabetic model (DM), low-dose perilla oil (LPO), middle-dose perilla oil (MPO), and high-dose perilla oil (HPO). C57BL/6J mice are fed a chow diet as normal control (NC). At the end of 12 weeks, mice are euthanized and glucolipid indications are analyzed. Gut microbiota analysis is carried out based on the sequencing results on V4 region of 16S rRNA. Although serum glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, abundance-based coverage estimator, and shannon are unchanged, serum triglyceride significantly decreases in LPO compared with DM. The histopathological changes of hepatocellular macrovesicular steatosis and adipocyte hypertrophy are ameliorated by perilla oil supplementation. Blautia is significantly decreased in LPO, MPO, and HPO, compared with DM. Nonmetric multidimensional scaling analysis shows NC and LPO are relatively coherent. CONCLUSION: These findings indicate that dietary supplementation with perilla oil can improve hypertriglyceridemia and gut dysbiosis in diabetic KKAy mice, which can be associated with potential benefits to human health.

Effects of Sanyaku and Its Constituent Diosgenin on the Fasted and Postprandial Hypertriacylglycerolemia in High-Fat-Diet-Fed KK- A y Mice.

In this study, we examined the fasted and postprandial triacylglycerol (TG) levels in KK- A y mice fed a high-fat diet (HFD) or a HFD containing either 500 ppm (0.05%) of diosgenin or 500 ppm (0.05%) of diosgenin-containing Chinese yam sanyaku. Oral fat tolerance tests revealed that, not only in the fasting state but also after loading of lipid emulsion, plasma levels of TG were significantly reduced in sanyaku- and diosgenin- fed mice. Levels of fat oxidation, especially in the dark phase (from 7 p.m. to 7 a.m.), were increased in the sanyaku and diosgenin groups. Moreover mRNA levels of lipoprotein lipase and peroxisome proliferator-activated receptor γ, coactivator 1α were moderately upregulated in the liver of sanyaku- and diosgenin-ingested mice. These results suggest that consecutive ingestion of diosgenin or diosgenin-containing sanyaku at the dose achievable in a human diet potentially ameliorates fasted and postprandial hypertriacylglycerolemia, which could be associated with the improvement of TG metabolism.

Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance.

Recent studies have demonstrated that dietary protein dilution (PD) can promote metabolic inefficiency and improve glucose metabolism. However, whether PD can promote other aspects of metabolic health, such as improve systemic lipid metabolism, and mechanisms therein remains unknown. Mouse models of obesity, such as high-fat-diet-fed C57Bl/6 N mice, and New Zealand Obese mice were fed normal (i.e., 20%P) and protein-dilute (i.e., 5%EP) diets. FGF21-/- and Cd36-/- and corresponding littermate +/+ controls were also studied to examine gene-diet interactions. Here, we show that chronic PD retards the development of hypertrigylceridemia and fatty liver in obesity and that this relies on the induction of the hepatokine fibroblast growth factor 21 (FGF21). Furthermore, PD greatly enhances systemic lipid homeostasis, the mechanisms by which include FGF21-stimulated, and cluster of differentiation 36 (CD36) mediated, fatty acid clearance by oxidative tissues, such as heart and brown adipose tissue. Taken together, our preclinical studies demonstrate a novel nutritional strategy, as well as highlight a role for FGF21-stimulated systemic lipid metabolism, in combating obesity-related dyslipidemia.

N-3 polyunsaturated fatty acids improve lipoprotein particle size and concentration in Japanese patients with type 2 diabetes and hypertriglyceridemia: a pilot study.

BACKGROUND: Patients with type 2 diabetes are at high risk for cardiovascular disease. Although hydroxymethylglutaryl-CoA reductase inhibitors (statins) can reduce cardiovascular events, residual risk remains even after target low-density lipoprotein cholesterol (LDL-C) levels have been achieved. Lipoprotein particle size and fraction changes are thought to contribute to such risks. The purpose of this study was to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), predominantly eicosapentaenoic acid and docosahexaenoic acid, on lipoprotein particle size, concentration, and glycemic control in Japanese patients with type 2 diabetes and hypertriglyceridemia. METHODS: This was a multicenter, prospective, open-label, single arm study. We enrolled 14 patients with type 2 diabetes and hypertriglyceridemia treated with statins and dipeptidyl peptidase-4 inhibitors with glycated hemoglobin (HbA1c) < 8.0%, LDL-C < 120 mg/dL, and fasting triglyceride ≥150 mg/dL. After a 12-week observation period, they were treated with 4 g/day n-3 PUFAs for 12 weeks. Lipoprotein particle sizes, concentrations, lipoprotein insulin resistance (LPIR) scores, lipid profiles, HbA1c, and fasting plasma glucose (FPG) were measured before and after treatment. Lipoprotein profiles were measured by nuclear magnetic resonance spectroscopy. Data were analyzed using Wilcoxon signed-rank tests. RESULTS: Concentrations of total cholesterol (P < 0.001), LDL-C (P = 0.003), and triglyceride (P < 0.001) decreased following n-3 PUFA administration. N-3 PUFAs decreased the size of very low-density lipoprotein (VLDL; P < 0.001) particles, but did not affect LDL or high-density lipoprotein (HDL) particles. The concentration of large LDL increased, whereas small LDL decreased, causing the large to small LDL ratio to increase significantly (P = 0.042). Large VLDL and chylomicron concentrations significantly decreased, as did the large to small VLDL ratio (all P < 0.001). FPG levels unchanged, whereas HbA1c levels slightly increased. LPIR scores improved significantly (P = 0.001). CONCLUSIONS: N-3 PUFAs partly improved atherogenic lipoprotein particle size and concentration, and produced less atherogenic lipoprotein subclass ratios in patients that achieved target LDL-C levels and glycemic control. These results suggest that n-3 PUFAs may reduce residual cardiovascular risk factors in statin-treated patients with type 2 diabetes and hypertriglyceridemia. TRIAL REGISTRATION: The study was registered at UMIN-ID: UMIN000013776 .

Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action.

For many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism. Since the pathogenesis of non alcoholic fatty liver disease (NAFLD) begins with the accumulation of liver lipid and progresses with inflammation and then several years later with development of fibrosis; it has been thought in patients with NAFLD omega-3 fatty acid treatment would be beneficial in treating liver lipid and possibly also in ameliorating inflammation. Meta-analyses (of predominantly dietary studies and small trials) have tended to support the assertion that omega-3 fatty acids are beneficial in decreasing liver lipid, but recent randomised controlled trials have produced conflicting data. These trials have suggested that omega-3 fatty acid might be beneficial in decreasing liver triglyceride (docosahexanoic acid also possibly being more effective than eicosapentanoic acid) but not in decreasing other features of steatohepatitis (or liver fibrosis). The purpose of this review is to discuss recent evidence regarding biological mechanisms by which long chain omega-3 fatty acids might act to ameliorate liver disease in NAFLD; to consider the recent evidence from randomised trials in both adults and children with NAFLD; and finally to discuss key 'known unknowns' that need to be considered, before planning future studies that are focussed on testing the effects of omega-3 fatty acid treatment in patients with NAFLD.

Agrimonia eupatoria L. (Agrimony) Extract Alters Liver Health in Subjects with Elevated Alanine Transaminase Levels: A Controlled, Randomized, and Double-Blind Trial.

Agrimonia eupatoria L. has been shown to protect against liver injury due to its lipid lowering and antioxidant activities. The aim of this research was to evaluate the effect of A. eupatoria L. aqueous extract (AEE) on 80 subjects with elevated alanine transaminase (ALT) levels in a randomized, double-blind, placebo-controlled, 8-week study. This trial was conducted between January 2013 and July 2013 at the Oriental Medical Hospital (Jecheon) of Semyung University. The trial included subjects aged 20 years or older who were diagnosed with mildly to moderately elevated ALT levels (between 45 and 135 IU/L). Subjects received two capsules of placebo or AEE twice a day for 8 weeks. Adverse events were recorded. Eighty subjects were randomized to placebo or AEE groups who had similar baseline characteristics. During the 8 weeks of treatment, 11 subjects were excluded from the analysis for protocol violation or consent withdrawal; efficacy of treatment was, therefore, evaluated in 69 subjects (placebo = 35, AEE = 34). The AEE group showed a significant reduction in ALT and serum triglyceride (TG) at 8 weeks compared with the placebo group (ALT P = .044, TG P = .020). Significant group and time interactions were found in ALT (P = .038), aspartate aminotransferase (P = .040), and TG (P = .010). Alkaline phosphatase, total bilirubin, and gamma-glutamyl transferase levels were not different between the two groups. There were no reported severe adverse events during this study, and total protein, albumin, blood urea nitrogen, creatine, and total cholesterol levels were normal in both groups. AEE consumption was safe and generally well tolerated without severe adverse events.

Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review.

BACKGROUND: Epidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies. METHODS: We conducted a review, using systematic methodology, of studies in humans assessing the mechanisms of action of EPA and DHA on apolipoprotein B-containing lipoproteins, including TG-rich lipoproteins and low-density lipoproteins (LDLs). A systematic search of PubMed retrieved 55 articles, of which 30 were used in the review; 35 additional arrticles were also included. RESULTS: In humans, dietary DHA is retroconverted to EPA, while production of DHA from EPA is not observed. Dietary DHA is preferentially esterified into TGs, while EPA is more evenly esterified into TGs, cholesterol esters and phospholipids. The preferential esterification of DHA into TGs likely explains the higher turnover of DHA than EPA in plasma. The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic very-low-density lipoprotein (VLDL)-TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely. The postprandial reduction in TG levels is caused by increased lipoprotein lipase activity and reduced serum VLDL-TG concentrations, resulting in enhanced chylomicron clearance. Overall, no clear differences between the effects of EPA and DHA on TG levels, or on turnover of TG-rich lipoproteins, have been observed. Effects on LDL are complex and may be influenced by genetics, such as APOE genotype. CONCLUSIONS: EPA and DHA diminish fasting circulating TG levels via reduced production of VLDL. The mechanism of reduced VLDL production does not involve hepatic retention of lipids. Lowered postprandial TG levels are also explained by increased chylomicron clearance. Little is known about the specific cellular and biochemical mechanisms underlying the TG-lowering effects of EPA and DHA in humans.