Bempedoic acid as a PPARα activator: new perspectives for hepatic steatosis treatment in a female rat experimental model. / El ácido bempedoico como activador PPARα: Nuevas perspectivas para el tratamiento de la esteatosis hepática en un modelo experimental de rata hembra.

INTRODUCTION: In its initial stages, nonalcoholic fatty liver disease presents hypertriglyceridemia and accumulation of lipids in the liver (hepatic steatosis). Bempedoic acid is an ATP:citrate lyase inhibitor that promotes a dual inhibition of the synthesis of cholesterol and fatty acids. However, its effect in the prevention / treatment of hepatic steatosis and hypertriglyceridemia has not been investigated. The aim of our work has been to elucidate whether bempedoic acid, through a mechanism other than ATP:citrate lyase inhibition, reverses these metabolic alterations. EXPERIMENTAL DESIGN: The study was carried out in female Sprague-Dawley rats fed, for three months, with a high fat diet supplemented with fructose (10% w/v) in drinking water. During the last month, bempedoic acid (30mg/kg/day) was administered to a group of animals. Zoometric and plasmatic parameters were analyzed, gene and protein expression analysis were performed in liver samples and PPAR-PPRE binding activity was determined. RESULTS: Our interventional model developed hepatic steatosis and hypertriglyceridemia. Despite an increase in total caloric intake, there was no increase in body weight of the animals. The administration of bempedoic acid significantly reduced hepatic steatosis and promoted a marked hepatocyte hypertrophy. There was a 66% increase in the liver weight of the animals treated with the drug that was not accompanied by modifications in the markers of inflammation, oxidative stress, or endoplasmic reticulum stress. Bempedoic acid activated the peroxisome proliferator activated nuclear receptor (PPARα) and its target genes. CONCLUSIONS: Bempedoic acid could be an effective therapy for the treatment of fatty liver and associated cardiovascular risk. Bempedoic acid has other mechanisms of action besides the inhibition of ATP: citrate lyase, such as the activation of PPARα, which could explain the reduction in hepatic steatosis and the increase in liver weight observed in animals treated with the drug.

Differing Nutrient Intake and Dietary Patterns According to the Presence of Hyper-Low-Density Lipoprotein Cholesterolemia or Hypertriglyceridemia.

Dietary choices may have differing effects on low-density lipoprotein cholesterol or triglyceride levels. The aim of this study was to investigate daily nutrient intake and dietary patterns of individuals with hyper-low-density lipoprotein cholesterolemia (hLDL) and hypertriglyceridemia (hTG) in a large Korean population-based study using propensity score (PS) matching. This study used data from the Korea National Health and Nutrition Examination Survey. Propensity score values for the predicted probability of patients with hLDL or hTG were estimated using logistic regression analysis, with age, sex, body mass index, alcohol consumption, smoking status, physical activity status, hypertension, and diabetes. After PS matching, intake of carbohydrates (%) was significantly lower (p = 0.021), and intake of fats (%) and saturated fatty acids (%) was significantly higher in the hLDL group than in the non-hLDL group (p = 0.025 and p = 0.013, respectively). The percentage of individuals with a high score for the Korean Healthy Eating Index (KHEI) "whole grains" or "saturated fatty acids" components was higher in the non-hLDL group than in the hLDL group (p < 0.05 for both). Dietary sodium/potassium ratio was significantly higher in the hTG than in the non-hTG (p = 0.049). Our results suggest that individualized dietary information and counseling require consideration of a person's specific lipid levels.

Potentially modifiable blood triglyceride levels by the control of conventional risk factors.

BACKGROUNDS: Triglyceride (TG) is known to be regulated by multiple lifestyle factors rather than genetic factors. This cross-sectional and community-based study (Healthy Twin study in Korea) aimed to estimate the "modifiable TG level" by identifying non-genetic risk factors of TG. METHODS: Participants were recruited between 2006 and 2011 who fulfilled health examinations and detail surveys: 3079 Korean adults including 949 monozygotic twins and 222 dizygotic twins. In order to investigate conventional risk factors, a mixed model accounting for family as a random effect was performed. In addition, we conducted a co-twin control analysis for 452 monozygotic twin (MZ) pairs, to examine non-genetic risk factors and potentially modifiable serum triglyceride levels. RESULTS: After excluding patients on dyslipidemia or diabetes medication, 2672 individuals (1029 men, with mean age of 43.9; and 1643 women with mean age of 43.3; 949 MZ pairs, 222 dizygotic twin pairs, and 1501sibling pairs) were analyzed. Fasting blood sugar (FBS), lipid panel, height, weight, waist (WC) and hip circumference, body mass index (BMI), amount of dietary intake and amount of physical activity was examined after adjusting for age and sex. For conventional analysis, WC, fat %, and BMI were identified as significant factors influencing serum triglyceride levels. Examination of non-genetic factors from the Co-twin control study revealed BMI (beta coefficient 9.94 with C.I. 3.42 to 16.46) and amount of alcohol intake (beta coefficient 0.08 with C.I. 0.02 to 0.14) as significant factors. CONCLUSION: Our findings suggest that controlling body weight and alcohol intake might be effective to control TG; moderate weight control (BMI 1 reduction) and reducing alcohol consumption by 50 g/week (about two glassed of beer) might reduce TG level by 9.94 and 4.0 mg/dL.

Lifestyle factors modulate postprandial hypertriglyceridemia: From the CORDIOPREV study.

BACKGROUND AND AIMS: Recent evidence suggests that postprandial hypertriglyceridemia (PPT) is associated with the incidence of CVD. Several non-modifiable factors (genetics, age, gender) and lifestyle factors (physical activity, smoking, regular alcohol) have shown their ability to modulate PPT. We evaluate the influence of regular alcohol intake, physical activity and smoking habit modulating PPT in the CORDIOPREV study (NCT00924937). METHODS: 1002 patients were subject to an oral fat load test meal and serial blood samples were drawn at 0, 1, 2, 3 and 4 h during postprandial state. A PPT concentration above 2.5 mmol/L (220 mg/dL) at any time point has been established as a detrimental response. Alcohol consumption was defined as non-drinkers, moderate and severe intake; regular physical activity exceeding than or lower than 1000 MET/week; smoking habit was classified in current, never, recent ex-smokers and long-term ex-smokers. RESULTS: The prevalence of undesirable PPT response was 68% in current, 58% in recent ex-smokers, 49% in long-term ex-smokers and 48% in never smokers (p < 0.001). Current and recent ex-smokers displayed higher PPT response as well as a greater area under the curve (AUC) and higher incremental (iAUC) of triglycerides (TG) compared with long-term ex-smokers and never smokers (p < 0.05), without differences among these subgroups. No differences were observed in the magnitude of PPT according to regular physical activity or alcohol intake habits. CONCLUSIONS: Smoking is an independent risk factor modulating the magnitude of PPT. However, after tobacco cessation, ex-smokers show a progressive decrease on their PPT to reach levels similar to those of never smokers.

Rutin and curcumin reduce inflammation, triglyceride levels and ADA activity in serum and immune cells in a model of hyperlipidemia.

Hyperlipidemia is associated with endothelial dysfunction and inflammatory disorders. Adenosine and adenosine deaminase (ADA) modulate immune responses and lipid metabolism. Curcumin and rutin are polyphenols with antioxidant, anti-inflammatory, and hypolipidemic effects. We evaluated the action of rutin and curcumin in the lipid levels and inflammation, as well as their effect on ADA activity in serum, lymphocytes, platelets, and neutrophils of hyperlipidemic rats. Adult male Wistar rats pretreated with curcumin and/or rutin for 30 days were submitted to Poloxamer-407- induced hyperlipidemia. Biochemical, hematological, and oxidative stress parameters, as well as serum and extracellular ADA activity, were performed 36h post-induction. Hyperlipidemia was confirmed by the increase in total cholesterol (TC) and triglycerides (TG). Hematological alterations, elevated reactive oxygen species (ROS) levels, and increased myeloperoxidase (MPO) and ADA activities were observed in hyperlipidemic rats. Curcumin and the curcumin/rutin association decreased TG and increased high-density lipids (HDL) levels. The pretreatments prevented changes in the hematological parameters, decreased the activities of MPO in plasma and ADA in serum and cells. Cholesterol and ROS levels were not altered by the pretreatments. Our results show that pretreatments with rutin and/or curcumin prevent the hyperlipidemia-induced inflammation. Pretreatments with curcumin and/or rutin are potential complementary therapies in the prevention of hypertriglyceridemia and inflammation.

Pistachio Consumption Prevents and Improves Lipid Dysmetabolism by Reducing the Lipid Metabolizing Gene Expression in Diet-Induced Obese Mice.

Pistachios contain beneficial substances such as unsaturated fatty acids, phytosterols, and polyphenols. In the present study, we investigated if pistachio consumption is able to prevent or to revert hyperglycemia, dyslipidemia, hepatic steatosis, and adipose tissue morphological alterations caused by high fat diet (HFD) in the mouse. Moreover, the impact of pistachio intake on the mRNA expression of peroxisome proliferator-activated receptor γ (PPAR-γ), fatty acid transport proteins (FAT-P), fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD1), and sterol regulatory element-binding transcription factor-1c (SREBP-1c) in liver and adipose tissue was also analyzed. No change in body weight, food intake, and hyperglycemia was observed between mice consuming pistachios (HFD-P) and HFD mice. Pistachio intake was able to prevent but not to reverse HFD-induced hypertriglyceridemia. Cholesterol plasma levels, steatosis grading, body fat mass, and adipocyte size were significantly lower in HFD-P group compared to HFD in both prevention and reversal protocol. Pistachio-diet was able to prevent HFD-induced overexpression of PPAR-γ, FAS, and SCD1 in the liver and SREBP-1c, PPAR-γ, and FAT-P in adipose tissue. Similarly, HFD-P significantly ameliorated the expression levels of FAT-P and SCD1 in the liver and SREBP-1c, FAS, and SCD1 in adipose tissue of obese mice. The present study shows that pistachio consumption is able to prevent and to ameliorate obesity-related dysfunctions by positively modulating the expression of genes linked to lipid metabolism.

Potential Involvement of Peripheral Leptin/STAT3 Signaling in the Effects of Resveratrol and Its Metabolites on Reducing Body Fat Accumulation.

Bioactive compounds such as polyphenols have increased in importance in recent years, and among them, resveratrol (3,5,4'-trihydroxy-trans-stilbene) has generated great interest as an anti-obesity agent. Recent investigations have highlighted the importance of leptin signaling in lipid metabolism in peripheral organs. The aims of this study were (1) to investigate whether resveratrol can reduce fat accumulation in peripheral tissues by increasing their leptin sensitivity and (2) to identify which resveratrol-derived circulating metabolites are potentially involved in these metabolic effects. Serum leptin levels and the leptin signaling pathway were assessed in diet-induced obese rats. Moreover, serum metabolites of resveratrol were studied by ultra-high performance liquid chromatography⁻mass spectrometry (UHPLC-MSn). The daily consumption of 200 mg/kg of resveratrol, but not doses of 50 and 100 mg/kg, reduced body weight and fat accumulation in obese rats and restored leptin sensitivity in the periphery. These effects were due to increases in sirtuin 1 activity in the liver, leptin receptors in muscle and protection against endoplasmic reticulum (ER)-stress in adipose tissue. In general, the resveratrol metabolites associated with these beneficial effects were derived from both phase II and microbiota metabolism, although only those derived from microbiota increased proportionally with the administered dose of resveratrol. In conclusion, resveratrol reversed leptin resistance caused by diet-induced obesity in peripheral organs using tissue-specific mechanisms.

Oral administration of lipid oil-in-water emulsions performed with synthetic or protein-type emulsifiers differentially affects post-prandial triacylglycerolemia in rats.

In this study, we compared the impact of administration of size-calibrated lipid emulsions prepared with either synthetic or natural emulsifiers on the post-absorptive plasma triacylglycerol responses in rats. We did this using four types of size-calibrated (10 µm diameter) and metastable (3 days) emulsions with 20% of an oleic acid-rich sunflower oil and 1% of either synthetic emulsifiers (Tween 80 or sodium 2-stearoyl-lactylate) or two proteins (ß-lactoglobulin or sodium caseinate). An oral fat tolerance test was performed in fasted rats by oral administration of each of these formulations in continuous or emulsified forms. Kinetic parameters (AUC0-inf., AUC0-6h, Cmax, Tmax, and T1/2) for the description of the plasma triacylglycerol responses were calculated. AUC0-6h and AUC0-inf. calculated for the protein groups were significantly lower than those of the control and the synthetic groups. These lower values were associated with significant decreases in the Cmax, exacerbated by the emulsion form and with marked decreases in the Tmax as compared to the control group. T1/2 values were differentially affected by the lipid administration forms and by the nature of the emulsifiers. As compared with the control group, T1/2 was largely increased in the sodium stearoyl-2-lactylate group, but on the contrary, largely lowered in the casein group. We concluded that the use of proteins as natural emulsifiers in lipid emulsions decreased the magnitude of post-prandial triacylglycerolemia for the same amount of ingested lipids, when the emulsion size is controlled for. Proteins could be a promising alternative to the widespread use of synthetic emulsifiers in the food industry.

Epigallocatechin-3-Gallate-Rich Green Tea Extract Ameliorates Fatty Liver and Weight Gain in Mice Fed a High Fat Diet by Activating the Sirtuin 1 and AMP Activating Protein Kinase Pathway.

The prevalence of metabolic diseases has risen globally in parallel with the obesity epidemic over the past few decades. Green tea has been reported to have metabolically beneficial effects on obesity; however, the mechanism by which green tea regulates lipid metabolism is not clearly understood. Male c57BL/6 mice were fed a normal chow diet, a high-fat diet (HFD), or an HFD supplemented with various doses of epigallocatechin gallate-rich green tea extract (GTE) for 12 weeks. GTE supplementation reduced body weight gain, prevented hepatic fat accumulation, decreased hypertriglyceridemia, and improved hyperglycemia and insulin resistance in HFD-fed mice. The underlying mechanisms of these beneficial effects of GTE might involve the upregulation of sirtuin 1 and AMP activated protein kinase (AMPK) and the downregulation of enzymes related to de novo lipogenesis. Consistent with the in vivo findings, GTE increased the expression and activity of sirtuin 1, enhanced the binding of sirtuin 1 to liver kinase B1 (LKB1) and subsequent deacetylation of LKB1, and reduced triglyceride accumulation in HepG2 cells. These results suggest the possible therapeutic potential of dietary epigallocatechin gallate-rich GTE supplementation for preventing the development and progression of hepatic steatosis and obesity.

Sports Practices and Cardiovascular Risk in Teenagers / Práticas Esportivas e Risco Cardiovascular em Adolescentes

Abstract Background: Cardiovascular diseases are the leading cause of deaths in the world, and many events could be prevented by healthy life habits. Objectives: To compare the occurrence of cardiovascular risk factors in adolescents enrolled at public schools in the city of Rio de Janeiro, including a renowned school for sport practices. Methods: Cross-sectional study, convenience sampling of 422 students enrolled at the Experimental Olympic Gymnasium (EOG) and at Figueiredo Pimentel School (FP). Using descriptive analyses, continuous variables were expressed as mean and standard deviation or median and interquartile ranges, and the Student's t-test or the chi-square test, respectively, was used for comparisons. The sports were classified according to the metabolic equivalent of task (MET) (below or above 5). Results: We included 274 students enrolled at the EOG and 148 at FP. Mean age was similar between schools -12.5 ± 1.6 years at FP and 12.6 ± 0.9 at the EOG; 65.5% of the students at FP and 43.8% of the students at the EOG were female (p < 0.01). Significant differences in the prevalence of hypertension (20% vs. 6.3%, p < 0.01) and borderline cholesterol levels (27.7% vs. 17.3%, p = 0.01) were found between FP and EOG students, respectively. Conclusion: High prevalence of hypertension, overweight/obesity and altered blood lipid profile was found in this group of adolescents. Regular sports training program combined with little influence of their eating habits outside school may contribute to a better metabolic profile and reduction in cardiovascular risk factors in students. Public health measures are also need.

Resumo Fundamento: As doenças cardiovasculares são a maior causa de mortes no mundo e muitos eventos poderiam ser evitados por meio de hábitos saudáveis de vida. Objetivos: Comparar a ocorrência de fatores de risco cardiovascular em adolescentes de escolas públicas do município do Rio de Janeiro, sendo uma delas, modelo em práticas esportivas. Métodos: Estudo transversal; amostra de conveniência de 422 escolares do Ginásio Experimental Olímpico (GEO) e da Escola Municipal Figueiredo Pimentel (FP). Foi realizada análise descritiva dos dados utilizando média e desvio-padrão (DP) ou mediana e intervalo interquartil para variáveis contínuas (testes t de Student e qui-quadrado para comparação, respectivamente). As modalidades esportivas foram classificadas de acordo com o equivalente metabólico (MET), se abaixo ou acima de 5. Resultados: duzentos e setenta e quatro alunos eram do GEO e 148 da FP. A média de idade era semelhante - 12,5 ± 1,6 na EMFP e 12,6 ± 0,9 no GEO; 65,5% dos alunos eram do sexo feminino na FP e 43,8% no GEO (p < 0,01). Da amostra geral, 40% apresentaram sobrepeso ou obesidade. Observaram-se diferenças entre a prevalência de hipertensão (20% vs. 6,3%; p < 0,01 nos alunos da FP e do GEO, respectivamente) e de níveis de colesterol total considerados limítrofes (27,7% vs. 17,3%; p = 0,01 na FP e no GEO, respectivamente). Conclusão: Hipertensão, sobrepeso/obesidade e lipidograma capilar alterado foram muito prevalentes nos adolescentes. Um programa de treinamento esportivo regular com menos interferência alimentar extraescola parece contribuir para um melhor perfil metabólico e menor risco cardiovascular entre estudantes. Ainda, medidas efetivas de saúde pública são necessárias.

Green Tea Polyphenol Epigallocatechin-3-gallate Suppresses Toll-like Receptor 4 Expression via Up-regulation of E3 Ubiquitin-protein Ligase RNF216.

Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (-)-epigallocatechin-3-O-gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) up-regulation. Our data indicate cyclic GMP mediates 67LR agonist-dependent RNF216 up-regulation. Moreover, we show that the highly absorbent 67LR agonist (-)-epigallocatechin-3-O-(3-O-methyl)-gallate (EGCG3″Me) significantly attenuated TLR4 expression in the adipose tissue. EGCG3″Me completely inhibited the high-fat/high-sucrose (HF/HS)-induced up-regulation of tumor necrosis factor α in adipose tissue and serum monocyte chemoattractant protein-1 increase. Furthermore, this agonist intake prevented HF/HS-induced hyperinsulinemia and hypertriglyceridemia. Taken together, 67LR presents an attractive target for the relief of obesity-induced inflammation.

Not every patient needs a triglyceride check, but all can get pancreatitis: a systematic review and clinical characterization of isotretinoin-associated pancreatitis.

Monitoring of triglycerides for patients on isotretinoin is practised primarily to avoid hypertriglyceridaemia-associated pancreatitis. The aim of this study was to describe clinically the published cases of hypertriglyceride-associated pancreatitis. A comprehensive search strategy using MEDLINE, Embase and grey literature was conducted (1960 to January 2016) to identify all case reports of isotretinoin-associated pancreatitis and all relevant studies of isotretinoin and triglycerides for any indication (≥ 20 patients). Terms related to isotretinoin, triglycerides and pancreatitis were searched with all available synonyms. Any studies that used isotretinoin and mentioned triglycerides or pancreatitis were searched in full text, where available, for cases of pancreatitis. Studies from all countries and published in any language were included, but Korean and Turkish studies could not be analysed. Two authors independently reviewed the publications to determine eligibility, and for data extraction. In total, 125 papers fulfilled the inclusion criteria and were searched for cases of pancreatitis. Eleven papers with 25 cases of pancreatitis associated with isotretinoin were identified; four of these cases were likely due to hypertriglyceridaemia. Three patients had elevated baseline triglycerides, but no monitoring. Pancreatitis occurred 6 and 7 weeks, and 6 months after initiation of therapy. For the fourth patient who was treated for glioblastoma and died, no detailed clinical information was available. Idiosyncratic pancreatitis associated with isotretinoin is the most frequent pancreatitis on isotretinoin, and patients should be warned about it. Hypertriglyceride-associated pancreatitis is an exceedingly rare adverse event of isotretinoin therapy. Our data cannot give a frequency or risk for either adverse event. Based on the clinical information of the patients available, we conclude that for patients without elevated baseline triglycerides, or risk thereof, monitoring of triglycerides during therapy is of little value.

Anthropometric Indicators in Hypertriglyceridemia Discrimination: Application as Screening Tools in Older Adults.

BACKGROUND AND PURPOSE: The use of anthropometric indicators as discriminators of hypertriglyceridemia has not been thoroughly investigated. The purpose of this article is to comparatively evaluate anthropometric indicators as discriminators of hypertriglyceridemia in older Brazilian adults. METHODS: This cross-sectional study derived from population-based epidemiological research involving 316 community-dwelling older adults (60-105 years old). RESULTS: Except for the conicity index and the body adiposity index in the group of women, all other anthropometric indicators (i. e., body mass index, waist and calf circumferences, triceps skinfold thickness, and waist-stature and waist-hip ratios) were sufficient to identify hypertriglyceridemia in the population. CONCLUSIONS: We endorse anthropometric indicators for use in screening for hypertriglyceridemia in older Brazilian adults.

A conjugated fatty acid present at high levels in bitter melon seed favorably affects lipid metabolism in hepatocytes by increasing NAD(+)/NADH ratio and activating PPARα, AMPK and SIRT1 signaling pathway.

α-Eleostearic acid (α-ESA), or the cis-9, trans-11, trans-13 isomer of conjugated linolenic acid, is a special fatty acid present at high levels in bitter melon seed oil. The aim of this study was to examine the effect of α-ESA on hepatic lipid metabolism. Using H4IIEC3 hepatoma cell line, we showed that α-ESA significantly lowered intracellular triglyceride accumulation compared to α-linolenic acid (LN), used as a fatty acid control, in a dose- and time-dependent manner. The effects of α-ESA on enzyme activities and mRNA profiles in H4IIEC3 cells suggested that enhanced fatty acid oxidation and lowered lipogenesis were involved in α-ESA-mediated triglyceride lowering effects. In addition, α-ESA triggered AMP-activated protein kinase (AMPK) activation without altering sirtuin 1 (SIRT1) protein levels. When cells were treated with vehicle control (VC), LN alone (LN; 100µmol/L) or in combination with α-ESA (LN+α-ESA; 75+25µmol/L) for 24h, acetylation of forkhead box protein O1 was decreased, while the NAD(+)/NADH ratio, mRNA levels of NAMPT and PTGR1 and enzyme activity of nicotinamide phosphoribosyltransferase were increased by LN+α-ESA treatment compared to treatment with LN alone, suggesting that α-ESA activates SIRT1 by increasing NAD(+) synthesis and NAD(P)H consumption. The antisteatosis effect of α-ESA was confirmed in mice treated with a high-sucrose diet supplemented with 1% α-ESA for 5weeks. We conclude that α-ESA favorably affects hepatic lipid metabolism by increasing cellular NAD(+)/NADH ratio and activating PPARα, AMPK and SIRT1 signaling pathways.

Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

BACKGROUND & AIM: Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. METHODS: Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. RESULTS: In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. CONCLUSION: While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis.

Omega-3 polyunsaturated fatty acids in treating non-alcoholic steatohepatitis: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: & aims: Few clinical trials have addressed the potential benefits of omega-3 polyunsaturated fatty acids (PUFAs) on non-alcoholic steatohepatitis (NASH). We evaluated the effects of supplementation with omega-3 PUFAs from flaxseed and fish oils in patients with biopsy-proven NASH. METHODS: Patients received three capsules daily, each containing 0.315 g of omega-3 PUFAs (64% alpha-linolenic [ALA], 16% eicosapentaenoic [EPA], and 21% docosahexaenoic [DHA] acids; n-3 group, n = 27) or mineral oil (placebo group, n = 23). Liver biopsies were evaluated histopathologically by the NASH activity score (NAS). Plasma levels of omega-3 PUFAs were assessed as a marker of intake at baseline and after 6 months of treatment. Secondary endpoints included changes in plasma biochemical markers of lipid metabolism, inflammation, and liver function at baseline and after 3 and 6 months of treatment. RESULTS: At baseline, NAS was comparable between the groups (p = 0.98). After intervention with omega-3 PUFAs, plasma ALA and EPA levels increased (p ≤ 0.05). However in the placebo group, we also observed increased EPA and DHA (p ≤ 0.05), suggesting an off-protocol intake of PUFAs. NAS improvement/stabilization was correlated with increased ALA in the n-3 group (p = 0.02) and with increased EPA (p = 0.04) and DHA (p = 0.05) in the placebo group. Triglycerides were reduced after 3 months in the n-3 group compared to baseline (p = 0.01). CONCLUSIONS: In NASH patients, the supplementation of omega-3 PUFA from flaxseed and fish oils significantly impacts on plasma lipid profile of patients with NASH. Plasma increase of these PUFAs was associated with better liver histology. (ID 01992809).

Role of adenosine 5'-monophosphate-activated protein kinase in α-linolenic acid-induced intestinal lipid metabolism.

n-3 Long-chain PUFA up-regulate intestinal lipid metabolism. However, whether these metabolic effects of PUFA on intestine are mediated by AMP-activated protein kinase (AMPK) remains to be elucidated. To determine the effects of α-linolenic acid (ALA) on intestinal fatty acid (FA) metabolism and whether these effects were affected by AMPK deletion, mice deficient in the catalytic subunit of AMPKα1 or AMPKα2 and wild-type (WT) mice were fed either a high-fat diet (HF) or HF supplemented with ALA (HF-A). The results showed that ALA supplementation decreased serum TAG content in WT mice. ALA also increased mRNA expression of genes (carnitine palmitoyltransferase 1a, acyl-CoA oxidase 1, medium-chain acyl-CoA dehydrogenase, cytochrome P450 4A10 and pyruvate dehydrogenase kinase isoenzyme 4a) involved in intestinal lipid oxidation and mRNA expression of TAG synthesis-related genes (monoacylglycerol O-acyltransferase 2, diacylglycerol O-acyltransferases 1 and 2) in WT mice. Consistent with these, expression levels of phosphorylated AMPKα1 and AMPKα2 were also increased in WT mice after ALA addition. However, in the absence of either AMPKα1 or AMPKα2, ALA supplementation failed to increase intestinal lipid oxidation. In addition, no significant effects of either diet (HF and HF-A) or genotype (WT, AMPKα1(-/-) and AMPKα2(-/-)) on FA uptake in the intestine and faecal TAG output were observed. Our results suggest that AMPK is indispensable for the effects of ALA on intestinal lipid oxidation.

Fruit and vegetable consumption and hypertriglyceridemia: Korean National Health and Nutrition Examination Surveys (KNHANES) 2007-2009.

BACKGROUND: Limited research has been conducted on the association between intake of fruits and vegetables and hypertriglyceridemia, especially in Asian populations. This study aimed to investigate the association between total fruit and vegetable intake, as well as subgroups of fruit and vegetable intake, with hypertriglyceridemia among Korean adults. METHODS: We conducted a cross-sectional study of 7934 adults aged 19-64 years from the fourth Korean Health and Nutrition Examination Survey. Fruit and vegetable intake was estimated from a food frequency questionnaire. Subgroups of fruits and vegetables included citrus, non-citrus and carotene-rich fruits and cruciferous, green leafy and carotene-rich vegetables. Hypertriglyceridemia (plasma triglyceride ⩾150 mg/dl) was diagnosed using a blood sample drawn after 12+ hours of fasting. RESULTS: There were 2001 (25.2%) cases of hypertriglyceridemia among the participants. Total fruit intake was significantly inversely associated with the prevalence of hypertriglyceridemia; the multivariate odds ratios (95% confidence intervals) of hypertriglyceridemia across increasing quintiles were 1.00 (ref), 0.76 (0.62, 0.92), 0.72 (0.58, 0.90), 0.68 (0.54, 0.85) and 0.64 (0.49, 0.82; Ptrend=0.001) after controlling for survey year, body mass index, waist circumference, smoking, alcohol drinking, physical activity, education and income. Similar inverse associations were found for all fruit subgroups. However, we found no significant association between intakes of total or subgroups of vegetable and hypertriglyceridemia; the odds ratio for top vs bottom quintile was 1.00 (0.81-1.24) for total vegetable intake. CONCLUSIONS: Our findings support a potential beneficial role of fruit consumption to reduce blood triglyceride levels in Asian populations.

Glucose- and Triglyceride-lowering Dietary Penta-O-galloyl-α-D-Glucose Reduces Expression of PPARγ and C/EBPα, Induces p21-Mediated G1 Phase Cell Cycle Arrest, and Inhibits Adipogenesis in 3T3-L1 Preadipocytes.

Plant polyphenols, such as hydrolysable tannins, are present in the human diet and known to exhibit anti-diabetic and anti-obesity activity. We previously reported that the representative hydrolysable tannin compound α-penta-galloyl-glucose (α-PGG) is a small molecule insulin mimetic that, like insulin, binds to insulin receptor (IR) and activates the IR-Akt-GLUT4 signaling pathway to trigger glucose transport and reduce blood glucose levels in db/db and ob/ob diabetic mice. However, its effects on adipogenesis and lipid metabolism were not known. In this study, high fat diet (HFD)-induced diabetic and obese mice were treated with α-PGG to determine its effects on blood glucose and triglycerides. 3T3-L1 preadipocytes were used as a cell model for identifying the anti-adipogenic activity of α-PGG at molecular and cellular levels as a first step in elucidating the mechanism of action of the compound. In vivo, oral administration of α-PGG significantly reduced levels of blood glucose, triglyceride, and insulin in HFD-induced diabetic/obese mice (P<0.05). In vitro, α-PGG inhibited the differentiation of 3T3-L1 preadipocytes into mature adipocytes. α-PGG suppressed the expression of positive adipogenic factors PPARγ C/EBPα and mTOR and augmented the negative adipogenic factor Pref-1. Furthermore, α-PGG induced upregulation of p21 and G1 phase cell cycle arrest. In contrast, adipogenic signaling pathways mediated by insulin, the cAMP response element binding protein (CREB) and glucocorticoid receptor (GR), were not inhibited. RNAi knockdown of p21 led to a 4-fold increase in triglyceride level in 3T3-L1 preadipocytes treated with MDI and α-PGG compared to regular preadipocytes. These results indicate, for the first time, that α-PGG is blood triglyceride- and glucose-lowering in HFD-induced obese and diabetic mice. It selectively inhibited some but not all major adipogenic pathways as well as the mTOR-p21-mediated cell cycle regulatory pathway. It is very likely that these apparently diverse but coordinated activities together inhibited adipogenesis. These results expand our knowledge on how PGG works in adipocytes and further confirm that α-PGG functions as an orally-deliverable natural insulin mimetic with adipogenetic modulatory functions.