Fasting Plasma TG Research Articles

The impact of short-term eucaloric low- and high-carbohydrate diets on liver triacylglycerol content in males with overweight and obesity: a randomized crossover study

BackgroundIntrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions. ObjectivesWe hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism. MethodsA randomized crossover trial in males with 4 d + 4 d of LC and HC, respectively, with ≥2 wk of washout. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of an LC diet (11E% carbohydrate corresponding to 102 ± 12 {mean ± standard deviation [SD]) g/d, 70E% fat} and an HC diet (65E% carbohydrate corresponding to 537 ± 56 g/d, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production and lipolysis, whole-body insulin sensitivity and substrate oxidation. ResultsEleven normoglycemic males with overweight or obesity (BMI 31.6 ± 3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95% confidence interval: −46.6, −24.1) from 4.9% [2.4–11.0] (median interquartile range) to 2.9% [1.4–6.9], whereas there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, whereas markers of de novo lipogenesis (DNL) diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index increased after LC. Peripheral glucose disposal was unchanged. ConclusionsReduced carbohydrate and increased fat intake for 4 d induced a marked reduction in liver TG content and increased hepatic insulin sensitivity. Increased rates of fat oxidation and ketogenesis combined with lower rates of DNL are suggested to be responsible for lowering liver TG. This trial was registered at clinicaltrials.gov as NCT04581421.

1654-P: Hepatic FGF21 Is Required for Curcumin and Resveratrol to Exert Their Metabolic Beneficial Effect in Male Mice

Intensive investigations have shown the profound metabolic beneficial effect of dietary intervention with plant polyphenols including curcumin and resveratrol. Recent studies have also shown that hepatic FGF21 is among the targets of dietary polyphenol intervention as well as intermittent fasting or nutritional restriction. Here we assessed whether hepatic FGF21 is required for dietary polyphenol intervention on metabolic homeostasis in mice on high fat high fructose diet (HFHF) challenge. Liver specific FGF21 null mice (Lfgf21-/-) were generated by mating Alb-Cre mice with Fgf21fl/fl mice. No appreciable defect on glucose disposal was observed in male or female Lfgf21-/- mice when they were fed with regular chow diet. In chow diet fed male but not female Lfgf21-/- mice, fat tolerance was impaired, associated with elevated fasting plasma TG level and reduced hepatic expression of Ehhadh and Ppargc1 (two downstream targets of FGF21). Following HFHF challenge, the control Fgf21fl/fl male mice exhibited response to 12-week curcumin intervention on reducing body weight, serum and hepatic TG elevation, and on improving fat tolerance. Those beneficial effects were absent in male Lfgf21-/- mice. In high fat diet challenged wild type mice, concomitant resveratrol intervention exhibited anticipated metabolic beneficial effect, associated with increased hepatic FGF21 mRNA and protein expression. Importantly, the metabolic beneficial effects of resveratrol intervention were observed in HFHF challenged Fgf21fl/fl mice but not in Lfgf21-/- mice. In wild type or transgenic female mice, we did not see appreciable beneficial effect with resveratrol intervention. Together we introduced a transgenic mouse model into the investigation of metabolic function of dietary intervention. We conclude that hepatic FGF21 is required for curcumin or resveratrol to exert its beneficial effect in male mice. Disclosure W.Shao: None. J.Feng: None. T.Jin: None. Funding Canadian Institutes of Health Research

MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies

Background and aimEnhanced hepatic de novo lipogenesis (DNL) has been proposed as an underlying mechanism for the development of NAFLD and insulin resistance. Max-like protein factor X (MLX) acts as a heterodimer binding partner for glucose sensing transcription factors and inhibition of MLX or downstream targets has been shown to alleviate intrahepatic triglyceride (IHTG) accumulation in mice. However, its effect on insulin sensitivity remains unclear. As human data is lacking, the aim of the present work was to investigate the role of MLX in regulating lipid and glucose metabolism in primary human hepatocytes (PHH) and in healthy participants with and without MLX polymorphisms. MethodsPHH were transfected with non-targeting or MLX siRNA to assess the effect of MLX knockdown on lipid and glucose metabolism, insulin signalling and the hepatocellular transcriptome. A targeted association analysis on imputed genotype data for MLX on healthy individuals was undertaken to assess associations between specific MLX SNPs (rs665268, rs632758 and rs1474040), plasma biochemistry, IHTG content, DNL and gluconeogenesis. ResultsMLX knockdown in PHH altered lipid metabolism (decreased DNL (p < 0.05), increased fatty acid oxidation and ketogenesis (p < 0.05), and reduced lipid accumulation (p < 0.001)). Additionally, MLX knockdown increased glycolysis, lactate secretion and glucose production (p < 0.001) and insulin-stimulated pAKT levels (p < 0.01) as assessed by transcriptomic, steady-state and dynamic measurements. Consistent with the in vitro data, individuals with the rs1474040-A and rs632758-C variants had lower fasting plasma insulin (p < 0.05 and p < 0.01, respectively) and TG (p < 0.05 and p < 0.01, respectively). Although there was no difference in IHTG or gluconeogenesis, individuals with rs632758 SNP had notably lower hepatic DNL (p < 0.01). ConclusionWe have demonstrated using human in vitro and in vivo models that MLX inhibition favored lipid catabolism over anabolism and increased glucose production, despite increased glycolysis and phosphorylation of Akt, suggesting a metabolic mechanism that involves futile cycling.

Correlation study on the relationship between dyslipidemia and carotid intima-media thickness in patients with diabetes mellitus.

To investigate the correlation between dyslipidemia and carotid intima-media thickness (IMT) in patients with diabetes mellitus. A descriptive research design was adopted in this study. One hundred and twenty patients with Type-2 diabetes mellitus who were admitted to the physical examination center of The Fourth Hospital of Hebei Medical University from June 2020 to June 2021 for physical examination were recruited to the experimental group. The 120 patients were divided into three groups according to carotid IMT: normal group, thickened group, and plaque group. Forty healthy people who underwent a physical examination during the same period were recruited as the control group. The differences in IMT in various parts of the experimental group and the control group and the differences in blood lipid indexes were compared and analyzed. In addition, the correlation between mean IMT of bilateral common carotid arteries and blood lipid levels in normal, thickened and plaque groups was compared and analyzed. The intima-media thicknesses of the internal carotid artery and bilateral common carotid arteries of the patients in the experimental group were significantly thicker than those in the healthy control group, the levels of TC, TG and LDL were higher than those in the control group, while the level of HDL was lower than that in the control group, with a statistically significant difference (p=0.00). The levels of fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), TG, TC and LDL were positively correlated with the mean IMT of bilateral common carotid arteries (p<0.05), while the level of HDL was negatively correlated with the mean IMT of bilateral common carotid arteries (p<0.05). Dyslipidemia and glucose metabolism in patients with Type-2 diabetes mellitus have a close bearing on carotid IMT. Clinically, patients with Type-2 diabetes mellitus can be judged by monitoring carotid IMT for dyslipidemia, atherosclerosis and other related complications.

Potential novel biomarkers in small intestine for obesity/obesity resistance revealed by multi-omics analysis

BackgroundAlthough obesity is caused by different factors, individual susceptibility to obesity differs among people under the same circumstances. The microbiota in the caecum or fresh faeces and metabolites in blood or urine contribute to obesity resistance; however, the microbiota or metabolites in the small intestine have not been extensively studied.MethodsTo investigate the relationship between the microbiota or metabolites in the small intestine and susceptibility to obesity, eighty-eight male C57BL/6 mice were fed a high-fat diet (HFD) for 8 weeks to establish two models of obesity and obesity resistance. For further study, six mice were chosen from among the obesity models, and twelve mice were randomly chosen from among the obesity resistance models. After fasting plasma glucose and behavioural testing, the mice were fed in single cages for another 4 weeks to observe their weight and food intake. All mice were sacrificed at 20 weeks of age. Serum ALT, AST, HDL, LDL, TG and TC levels were measured using an automatic biochemical analyser. The microbiota and metabolites in the small intestine contents were analysed using 16 S sequencing and an ultrahigh-performance liquid chromatographic system, respectively. Transcripts in the jejunum were evaluated using full-length transcriptome sequencing and verified by qPCR.ResultsThe results showed that HFD induced depression and anxiety behaviours and higher fasting plasma glucose, ALT, AST, HDL, LDL, TG and TC levels in the obese mice; however, these levels were improved in obese resistance mice. The correlation analysis showed that the phosphatidylcholine, TG, and phosphatidylethanolamine levels were higher in obese mice and correlated positively with intestinal microflora (Desulfovibrio and Gemella) and the Cxcl10 gene. A higher abundance of Clostridium_sensu_stricto_1 in obesity-resistant mice correlated negatively with the metabolite contents (neuromedin N and enkephalin L) and Pck1 gene expression and correlated positively with certain metabolites (5-hydroxy-L-tryptophan, cinnamyl alcohol and 1 H-indole-3-acetamide) and genes expression (Gdf15, Igfbp6 and Spp1).ConclusionClostridium_sensu_stricto_1, neuromedin N, enkephalin L, Pck1, 5-hydroxy-L-tryptophan, Cxcl10 and cinnamyl alcohol may be novel biomarkers in the small intestine for obesity/obesity resistance. These might be helpful for obesity prevention or for treating obese patients.

GLP-1 attenuates intestinal fat absorption and chylomicron production via vagal afferent nerves originating in the portal vein

Background/ObjectiveGLP-1R agonists have been shown to reduce fasting and postprandial plasma lipids, both of which are independent risk factors for the development of cardiovascular disease. However, how endogenous GLP-1 – which is rapidly degraded – modulates intestinal and hepatic lipid metabolism is less clear. A vagal gut-brain-axis originating in the portal vein has been proposed as a possible mechanism for GLP-1’s anti-lipemic effects. Here we sought to examine the relationship between vagal GLP-1 signalling and intestinal lipid absorption and lipoprotein production. MethodsSyrian golden hamsters or C57BL/6 mice received portal vein injections of GLP-1(7-36), and postprandial and fasting plasma TG, TRL TG, or VLDL TG were examined. These experiments were repeated during sympathetic blockade, and under a variety of pharmacological or surgical deafferentation techniques. In addition, hamsters received nodose ganglia injections of a GLP-1R agonist or antagonist to further probe the vagal pathway. Peripheral studies were repeated in a novel GLP-1R KO hamster model and in our diet-induced hamster models of insulin resistance. ResultsGLP-1(7-36) site-specifically reduced postprandial and fasting plasma lipids in both hamsters and mice. These inhibitory effects of GLP-1 were investigated via pharmacological and surgical denervation experiments and found to be dependent on intact afferent vagal signalling cascades and efferent changes in sympathetic tone. Furthermore, GLP-1R agonism in the nodose ganglia resulted in markedly reduced postprandial plasma TG and TRL TG, and fasting VLDL TG and this nodose GLP-1R activity was essential for portal GLP-1s effect. Notably, portal and nodose ganglia GLP-1 effects were lost in GLP-1R KO hamsters and following diet-induced insulin resistance. ConclusionOur data demonstrates for the first time that portal GLP-1 modulates postprandial and fasting lipids via a complex vagal gut–brain–liver axis. Importantly, loss or interference with this signalling axis via surgical, pharmacological, or dietary intervention resulted in the loss of portal GLP-1s anti-lipemic effects. This supports emerging evidence that native GLP-1 works primarily through a vagal neuroendocrine mechanism.

Gestational hypertriglyceridemia and adverse pregnancy outcomes: A search for cutoffs using generalized additive models

ObjectiveTo explore cutoffs of gestational hypertriglyceridemia based on the risk of adverse pregnancy outcomes. MethodsPregnant women who visited National Taiwan University Hospital for prenatal care were included. Fasting plasma TG in the first and second trimesters were measured. Adverse pregnancy outcomes, including gestational diabetes and large for gestational age, were recorded and used in simple and multiple generalized additive models (GAM) to identify cutoffs for gestational hypertriglyceridemia. ResultsWe recruited 807 pregnant woman-newborn pairs. Using GAM analyses, we identified plasma TG at 95 or 140 mg/dL (1.07 or 1.58 mmol/L) in the first trimester, and 173 or 220 mg/dl (1.95 or 2.48 mmol/L) in the second trimester as potential cutoffs. Gestational hypertriglyceridemia defined by the higher cutoffs in both trimesters were associated with adverse pregnancy outcomes and had a more reasonable prevalence and better specificity than the lower cutoffs (First trimester plasma TG ≥ 140 mg/dL, adjusted OR 2.56, 95% CI 1.17–5.69, p = 0.019, prevalence 19%, specificity 83%; Second trimester plasma TG ≥ 220 mg/dL, adjusted OR 1.70, 95% CI 1.00–2.87, p = 0.049, prevalence 19%, specificity 81%). ConclusionsFasting plasma TG ≥ 140 mg/dL in the first trimester and ≥ 220 mg/dL in the second trimester can be used as cutoffs of gestational hypertriglyceridemia.

SUN-022 Metformin-Fish Oil Adjunct Therapy Improves apoB-Remnant Lipoprotein and Triglyceride Levels in Women with Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is highly associated with the metabolic syndrome (MetS): obesity, insulin resistance and atherogenic dyslipidemia. Women with PCOS-MetS are at higher risk of developing ischemic cardiovascular disease (CVD) and Type-2 Diabetes. First-line intervention in PCOS-MetS includes targeting diet and lifestyle, and metformin is commonly prescribed to treat insulin resistance, however these interventions have shown limited effectiveness to improve dyslipidemia. At present there are limited safe and efficious options to target atherogenic dyslipidemia in young women with PCOS. Fish oil (FO) and Icosapentyl ethyl supplementation have been shown to reduce fasting TG, apoB and to improve ischemic CVD outcomes. The efficacy of FO or as an adjunct therapy to metformin to improve ApoB-remnant lipemia in PCOS-MetS is unknown. The aim of this pilot study was to determine the effect of metformin, FO and FO-metformin combination treatment on fasting and non-fasting plasma TG and apoB-remnant lipoprotein metabolism in patients with PCOS-MetS. Methods: Participants diagnosed with PCOS aged 18-30yrs received dietary counselling and were randomly assigned to receive FO (n=8), metformin (n=7) or FO-metformin (n=12) treatment for 12 wks. Plasma lipids (TG and cholesterol), ApoB48 and ApoB100 lipoprotein metabolism were assessed in the fasting and non-fasting state using a standardized high-fat meal test. Results: At baseline, the fasting plasma TG, ApoB48 and ApoB100 was 238.0 ± 21.0 mg/dL, 9.00 ± 1.12 ug/ml and 290 ± 18.00 mg/dL. FO and FO-metformin decreased fasting plasma TG by 10% and 30% compared to the metformin treatment group (7%). Fasting ApoB48 was reduced 45%, 16% and 19% in FO-metformin, FO and metformin treatment groups, respectively. Non-fasting plasma TG and apoB48 lipoprotein area under the curve were reduced by 30% in the FO-metformin treatment group. Conclusion: These pilot findings demonstrate FO-metformin adjunct therapy may have greater efficacy to improve atherogenic apoB-dyslipidemia compared to metformin or FO alone in high-risk patients with PCOS-MetS. A larger clinical trial is warranted to determine the long term effects of FO-metformin intervention on apoB-dyslipidemia and atherosclerotic cardiovascular disease indices.

Exercise Training Adaptations in Metabolic Syndrome Individuals on Chronic Statin Treatment.

Statins reduce atherogenic dyslipidemia and cardiovascular disease (CVD) risk in metabolic syndrome (MetS) individuals. Exercise training could also contribute to reduce CVD by improving cardiorespiratory fitness and fat oxidation. However, statin use could interfere with training adaptations. A total of 106 MetS individuals were divided into statin users (statin group, n = 46) and statin-naïve (control group, n = 60). Groups were matched by age, weight, and MetS components. Subjects completed 16 weeks of high intensity interval training (HIIT). Before and after HIIT, muscle biopsies were collected to assess mitochondrial content (citrate synthase [CS] activity) and the activity of the rate limiting β-oxidation enzyme (3-hydroxyacyl-CoA-dehydrogenase [HAD]). Fasting plasma glucose, insulin, TG, HDL-c, and LDL-c concentrations were measured. Exercise maximal fat oxidation (FOMAX) and oxygen uptake (VO2PEAK) were determined. Training improved MetS similarly in both groups (MetS z-score -0.26 ± 0.38 vs. -0.22 ± 0.31; P < 0.001 for time and P = 0.60 for time x group). Before training, the statin group had reduced muscle HAD activity and whole body FOMAX compared to the control group. However, 16 weeks of HIIT increased HAD and FOMAX in both groups (P < 0.03, time-effect). The statin group did not prevent the increases in CS with HIIT observed in the control group (38% vs 64%, respectively; P < 0.001, time-effect). Conversely, with training VO2PEAK improved less in the statin than in the control group (12% vs. 19%, respectively; P = 0.013, time × group effect). Chronic statin use in MetS does not interfere with exercise training improvements in MetS components, FOMAX, or mitochondrial muscle enzymes (ie, CS and HAD). However, the statin group attenuated the improvements in VO2PEAK with training. ClinicalTrials.gov identifier no. NCT03019796, January 13, 2017.

Association of GCKR Gene Polymorphisms with the Risk of Nonalcoholic Fatty Liver Disease and Coronary Artery Disease in a Chinese Northern Han Population.

Background and Aims: Accumulated studies have evaluated the effects of glucokinase regulatory protein (GCKR) gene polymorphisms on the risk of nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD), but the association of GCKR polymorphisms with the risk of NAFLD and CAD in the Chinese Han population have remained unclear. The aim of this study was to investigate the association between GCKR gene polymorphisms (rs780094 and rs1260326) and the risk of NAFLD and CAD in NAFLD patients in a Chinese Northern Han population.Methods: GCKR rs780094 and rs1260326 gene polymorphisms were genotyped by polymerase chain reaction sequencing for B-type ultrasonography-proven NAFLD patients with (n = 82) or without (n = 142) CAD, and in healthy controls (n = 152). Serum lipid profiles’ levels were determined using biochemical methods. Statistical analyses were conducted using SPSS 22.0 statistical software.Results: As the results showed, significant differences in the serum lipid profiles existed between each group. No significant differences were observed in the distributions of genotypes and alleles of GCKR rs780094 and rs1260326 in each group. The GCKR rs780094 T and rs1260326 T allele carriers possessed decreased body mass index value, and serum fasting plasma glucose and TG levels in the overall subjects, respectively. In addition, the GCKR rs780094 T allele carriers possessed decreased serum fasting plasma glucose level in the controls and NAFLD + CAD patients.Conclusions: GCKR rs780094 and rs1260326 polymorphisms were found to be not associated with the risk of NAFLD nor of CAD in NAFLD patients in this Chinese Northern Han population. GCKR rs780094 T and rs1260326 T alleles could affect the body mass index value and serum fasting plasma glucose and triglyceride levels.

Prediction of 5-year risk of diabetes mellitus in relatively low risk middle-aged and elderly adults.

To determine the potential risk factors and construct the predictive model of diabetic risk among a relatively low risk middle-aged and elderly Chinese population. Information of participants was collected in the Dongfeng-Tongji cohort study, a perspective cohort study of Chinese occupational population. The main outcome was incident type 2 diabetes (T2DM). Based on the conventional risk factors of diabetes, we defined low risk participants without underlying diseases such as coronary heart disease, stroke, cancer, dyslipidemia, hypertension, metabolic syndrome, obesity and family history of diabetes. Totally, 4833 participants from the Dongfeng-Tongji cohort study were enrolled, and of them, 171 had an incident diagnosis of T2DM during 4.6years of follow-up period. A Cox proportional hazards model was used to estimate effects of risk factors. The restricted cubic spline regression and the Youden index were used to explore the optimal cutoffs of risk factors, and the C index was used to assess the discrimination power of prediction models. There were significant linear relationships between BMI/TG level/fasting glucose level and incident diabetic risk among low risk participants. In the restricted cubic spline regression, when fasting glucose level was above 5.4mmol/L, TG above 1.06mmol/L and BMI above 22kg/m2, the HRs (95% CIs) of diabetes were above 1.0. The detailed HRs (95% CI) were 1.29 (1.01, 1.64), 2.57 (1.00, 6.58), and 1.49 (1.00, 2.22), respectively. The optimal cutoff determined by the Yonden index was 1.1mmol/L for TG, 24kg/m2 for BMI and 5.89mmol/L for fasting plasma glucose, respectively. The C index was 0.75 (95% CI: 0.7-0.81) when age, sex, smoke status, physical activity, BMI (< 24kg/m2 and ≥ 24kg/m2), TG (< 1.1mmol/L and ≥ 1.1mmol/L), and FPG (< 5.89mmol/L and ≥ 5.89mmol/L) were introduced into the diabetes predictive model. Fasting plasma glucose level, BMI, and triglyceride level were still dominated factors to predict 5-year diabetic risk among the relatively low risk participants. The cutoff values for fasting plasma glucose, TG, and BMI set as 5.89mmol/L, 1.1mmol/L, and 24kg/m2, respectively, had the best predictive discrimination of diabetes.

Feruloylated oligosaccharides from maize bran alleviate the symptoms of diabetes in streptozotocin-induced type 2 diabetic rats.

This study investigated the therapeutic effect of feruloylated oligosaccharides (FOs) extracted from maize bran on type 2 diabetic rats and its potential mechanism. Streptozotocin (STZ) induced type 2 diabetic male rats were orally administered with different levels of FOs for 8 weeks, and ferulic acid (FA) treatment was conducted as the positive control. Among all the treatments, the oral administration of 600 mg per kg bw per d FOs showed the best therapeutic effects on the diabetic rats by significantly lowering the levels of fasting plasma glucose (FPG), fasting insulin, TG, LDL-c, aspartate transaminase, creatine kinase and lactate dehydrogenase in plasma, while increasing the level of plasma HDL-c. In addition, the intake of FOs at 600 mg per kg bw per d exhibited the best antioxidant effects in the plasma, liver, kidney and heart of the diabetic rats, and the highest inhibitory effects on the formation of AGEs and CML in the organs, which might explain the alleviating effects of FOs on abdominal aorta injury observed in the current study. FOs presented better regulation effects on FPG, plasma lipid and the protection of abdominal aorta than FA under the same administered dosage. Based on these outcomes, FOs from maize bran could be beneficial for prevention or early treatment of diabetes mellitus.

Abstract 18: APOBEC1 Complementation Factor: A Novel Regulator of Triglyceride Metabolism

A recent human rare-variant study on plasma lipids has identified a missense mutation in the A1CF (APOBEC1 complementation factor) gene that significantly associates with TG levels. Expressed in the liver and small intestine, A1CF encodes an RNA binding protein that facilitates APOBEC1’s editing of APOB mRNA, introducing a premature stop codon that yields apoB-48. Surprisingly, despite the importance of apoB-48 in plasma lipid metabolism, prior studies have shown that APOBEC1 deficiency itself does not alter plasma TG levels. Therefore, we hypothesize that A1CF regulates TG metabolism independently of its role in APOB mRNA editing. To evaluate this hypothesis, we used CRISPR-Cas9 to generate whole-body A1cf knockout mice ( A1cf - / - ), knock-in mice homozygous for the TG-associated Gly398Ser mutation ( A1cf GS/GS ), and A1cf - / - rat hepatoma cell lines. Both A1cf GS/GS and A1cf - / - mice had significantly increased fasting plasma TG compared to controls (1.71-fold, N = 22-27, P = 1.5 х 10 -3 ; and 1.67-fold, N = 15-27, P = 1.8 х 10 -3 respectively), recapitulating the human TG phenotype and demonstrating that A1CF loss of function leads to hyperTG. Supporting our hypothesis that this occurs independently of APOBEC1 function, apoB-48 was detected by immunoblot in the plasma and small intestines of A1cf - / - and A1cf GS/GS mice without a significant shift in apoB-100/apo-B48. TG clearance was not decreased in A1cf - / - mice during an oral fat tolerance test (N = 12), but A1CF deficiency did result in increased TG secretion in vivo (1.34-fold, N = 12, P &lt; 0.001), consistent with an observed increase in VLDL-apoB secretion by A1cf - / - hepatoma cells (1.55-fold, P &lt; 0.001). We performed RNA-seq of A1cf - / - and wild-type mouse livers, and while differential expression analysis did not yield candidate mechanisms to explain the TG phenotype, we detected 167 alternative splicing (AS) events (delta PSI &gt; 10). We validated several AS events for metabolism genes such as Khk and Hmgcl by RT-PCR, identifying A1CF’s previously unknown role as a regulator of AS events with clear metabolic relevance. In summary, we have demonstrated in our functional follow-up of a human rare-variant study that A1CF modulates TG metabolism through entirely novel mechanisms independent of APOB mRNA editing.

Effect of daily calcitriol supplementation with and without calcium on disease regression in non-alcoholic fatty liver patients following an energy-restricted diet: Randomized, controlled, double-blind trial

Despite evidence for beneficial effects of vitamin D, to our knowledge, no study has compared the effects of calcium supplementation with vitamin D on non-alcoholic fatty liver disease (NAFLD) regression during a hypo-energetic program. We compared the effect of the vitamin D supplementation with and without calcium on anthropometric measures and biochemical parameters in NAFLD patients during a weight-loss program. A 12-week, randomized, controlled, double-blind trial was conducted in 120 NAFLD patients randomly assigned to receive 25μg calcitriol (n=37), 500mg calcium carbonate+25μg calcitriol (n=37), or placebo (n=36) every day with their lunch meals while following a weight-loss program. Weight, BMI and fat mass reduction were significant in each group after 12wk of intervention (p<0.001), but differences among the groups was not significant after 12wk of the study, adjusted to the baseline measurements. Significant reduction in fasting plasma glucose (FPG), insulin, insulin resistance (by HOMA-IR) and TG concentrations and an increase in HDL.C was seen over the 12wk of study in each group (p<0.001). Adjusting to the baseline measurements, there was significant difference in FPG (p<0.001), HOMA-IR (p<0.001), serum insulin (p=0.01), TG (p=0.01) and HDL.C (p<0.001) among the groups after 12wk of the study. The calcium plus calcitriol group showed a significant decrease in ALT and FPG and increase in HDL.C level compared with the calcitriol group, adjusted to the baseline measures (p<0.001). Our results suggest that calcium plus calcitriol supplementation for 12 weeks may be potentially effective for biochemical parameters in NAFLD patients. Further additional larger controlled trials are needed to confirm these findings. Registered under ClinicalTrials.gov Identifier no. IRCT201408312709N29.

Significance of normal range urinary albumin to creatinine ratio in Chinese subjects with metabolic syndrome.

This study was aimed to investigate clinical features of Chinese metabolic syndrome (MS) subjects with normal urinary albumin to creatinine ratio (UACR) and to estimate independent correlation factor for UACR. Data were drawn from a cross-sectional survey in participants having MS. The patients with different grade of albuminuria were divided into 4 groups according to the value of UACR (<10, 10-20, 21-30, >30 mg/g). All underwent biochemical tests. Bioelectrical impedance body fat content, islet β-cell function and insulin sensitivity were measured. Multivariable linear regression models were applied to further determine association between UACR and clinical factors with adjustment. Systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), fasting plasma glucose (FPG), glycosylated hemoglobin (HbA1c), TG, fat mass, fat content and homeostasis model assessment for insulin resistance (HOMA-IR) were significantly higher in the group with UACR at 10-20 mg/g than those in the group with UACA lower than 10 mg/g (P<0.05). Multivariable linear regression showed that TG, HbA1c, waist-hip ratio (WHR) and SBP were independently associated with UACR. The patients with normal UACR had abnormal levels of MS components. The factors independently associated with UACR were TG, HbA1c, WHR and SBP.

Diabetic cardiomyopathy in medical examination patients with impaired glucose tolerance and Type 2 diabetes

To investigate the change of diabetic cardiomyopathy in patients with impaired glucose tolerance (IGT) and Type 2 diabetes (T2DM) and its influencing factors. Patients with IGT and T2DM were divided into an IGT group (n=314), a T2DM group (n=368) and an NC group (400 normal subjects). The left ventricular ejection fractions (LVEF) and the interventricular septal depth (IVSd) were measured by Doppler echocardiography. The general information and blood biochemistry were also collected during the corresponding time period. Compared with the NC group, waist circumference (WC), bodymass index (BMI), premature family history of cardiovascular disease, the serum levels of fasting plasma glucose (FPG), HbA1c, TC, TG, hyperlipidemia, BUN and Cr significantly increased (P<0.01) in the IGT and T2DM groups. Compared with the NC group and the IGT group, the LVEF significantly decreased (P<0.01) and the IVSd significantly increased (P<0.01) in the T2DM group. The LVEF and IVSd did not have obvious difference between the NC group and the IGT group. Pearson correlation analysis showed a negative correlation between LVEF and HbA1c, TC and duration of disease (P<0.01); but a positive correlation between IVSd and WC, BMI, HbA1c and duration of disease, and a negative correlation between IVSd and HDL (P<0.05). In the multiple linear stepwise regression, HbA1c and duration of disease showed a significant association with both LVEF and IVSd (P<0.05). T2DM has a close association with cardiomyopathy. HbA1c and duration of disease are the independent predictors for LVEF and IVSd.

Abstract 10: Improving Postprandial Lipoprotein Apolipoprotein B-48 Metabolism in Statin-Treated Patients With Diabetes

Background: Type 2 diabetics often have elevated plasma TG and apolipoprotein B-48 (apoB-48) concentrations, particularly during the postprandial (PP) period. Evidence suggests that apoB-48 plays a central role in the development of atherosclerosis. Statins are frontline therapy to reduce CVD risk, however, residual risk still remains, suggesting that additional interventions are required to further reduce CVD risk. Aim: To compare PP apoB-48 kinetics in optimally statin-treated diabetic men with a group of normolipidemic healthy controls, and to investigate the effect of niacin on apoB-48 kinetics in these diabetic men. Methods: Twelve type 2 diabetic men and fourteen age-matched non-diabetic controls were recruited. Diabetics required a statin-treated LDL-C &lt; 2.5 mmol/L to enter the trial: they were randomized to rosuvastatin or rosuvastatin plus niacin (titrated from 1 to 2 g daily) for 12 weeks and then crossed to the alternate therapy (3 week washout). PP metabolic studies were performed at the end of each treatment period, and on a single occasion in control subjects. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. Blood samples were collected over 24 h. ApoB-48 tracer/tracee ratios were measured using GCMS. Kinetic parameters, including fractional catabolic rate (FCR) and production rate (PR), were derived using a compartmental model. Results: Fasting plasma TG (+112%, p&lt;0.01), but not apoB-48 was elevated in statin-treated diabetics compared with controls. Incremental AUC TG and apoB-48 (+194% and +79%, respectively, p&lt;0.01) were higher in diabetics. PP apoB-48 PR was higher in diabetics (+96%, p&lt;0.01) and FCR lower (-45%, p&lt;0.05), compared with controls. Niacin significantly lowered TG, plasma C, LDL-C and apoB (all p&lt;0.005). Fasting apoB-48 concentration was lowered with niacin (-33%, p=0.03). ApoB-48 FCR was not altered with niacin, but PP apoB-48 PR was lowered to control levels (-38%, p=0.02) on niacin. Conclusion: ApoB-48 PR and FCR are abnormal in statin-treated diabetics. Niacin reduces apoB-48 concentration by lowering apoB-48 PR. This effect may be beneficial for reducing atherogenic PP lipoproteins and may provide CVD risk benefit to patients with type 2 diabetes.

COLT, Multicenter CaPre Open Label Randomized Dose-Ranging Phase II Trial to Assess Efficacy/Safety in Patients with Mild-to-High Hypertriglyceridemia

Background: Long-chain polyunsaturated omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to reduce hepatic secretion of TG rich lipoproteins and plasma TG levels. CaPre® is a novel highly purified omega-3 krill oil extract with a high content of EPA and DHA phospholipid conjugates. Objective/Purpose: To evaluate the efficacy of CaPre® to reduce fasting plasma TG ranging between 200-877 mg/dL after 4 and 8 weeks vs. Standard Of Care (SOC). Additional endpoints were changes in TC, LDL-C, HDL-C, non-HDL-C, and HbA1c. Methods: Total of 288 patients from 34 centers aged 18-75 were randomized to Standard of Care (SOC), or CaPre® given daily with dose doubling at week 4 for 0.5g, 1g, and 2g groups while the 4g group was dosed for 8 weeks. Standard safety assessments were performed during the trial. Statistical analysis was performed using ANOVA followed by post-hoc contrast analysis assessing % change between baseline, week 4 and 8 with CaPre® compared to SOC. Results: CaPre® SOC-compared 4-week TG % difference was -8% (p=NS), -16% (p=0.007), -13% (p=0.025) and -18% (p=0.002), for 0.5g, 1g, 2g, and 4g, respectively, while the SOC-compared 8-week TG % difference was 2% (p=NS), 16% (p=0.021), -6% (p=NS) and -14% (p=0.038), for 0.5g, 1g, 2g, and 4g, respectively. CaPre® 4g SOC-compared 8-week TC % difference was -7% (p=0.06) and while the nonHDL-C was -10% (p=0.036). Similarly to beneficial lipid effects, HbA1c was significantly lowered with CaPre® 2g (-18%, p=0.013) and 4g (-15%, p=0.039). CaPre® was safe, well-tolerated, with incidence of AEs similar to SOC. Conclusions: CaPre® at daily doses of 1g-4g was effective and safe in reducing serum triglycerides and increasing HDL-C without deleterious effects on increasing LDL-C in patients with mild-to-high hypertriglyceridemia (NCT01516151).

Abstract 632: Lipoprotein Lipase Activators: A New Potent Drug Class for Treatment of Dyslipidemia

Aim: Elevated plasma TG and low HDL-cholesterol are part of CVD residual risk. Lipoprotein lipase (LPL) is the central enzyme controlling plasma TG hydrolysis and affecting de novo HDL formation. Thus LPL is an attractive target for correcting dyslipidemia and reduction of CVD residual risk. We have identified a novel first-in-class small molecule LPL activator - LP071. The objective with this study was to characterize the plasma lipid metabolism in LPL activator treated mice. Methods: ApoE3L:CETP mice were treated week with LP071. Plasma lipid profiles were analyzed using FPLC fractioning. LPL activity was investigated systemically and in specific tissue. Using triton WR1339 blockade chylomicron and VLDL secretion were assessed. Functional lipid clearance test were performed by oral fat tolerance tests. Results: Fasting plasma TG levels decreased with 97 % in apoE3L:CETP mice treated with LP071; HDL-c were increased by 116 % and (V)LDL-c were decreased with 91 %. Plasma free glycerol and NEFA were significantly lowered, 26 % and 22 % respectively. After an oral lipid load the plasma lipid response was significantly blunted in LP071 treated mice compared to controls. LPL activity in subcutaneous adipose tissue was increased 1500 % and in BAT LPL was increased by 100% at 3 h after a lipid gavage in WT mice treated with LP071. Conclusions: LP071 is a potent compound that can improve plasma lipid levels to a less atherogenic profile. The LP-class LPL activators can potentially help battle CVD residual risk in the future.

Circulating Chemerin Levels are Increased in First-Degree Relatives of Type 2 Diabetic Patients

Chemerin is an important risk factor of insulin resistance and metabolic syndrome. The aim of this study was to explore the potential role of chemerin in the early stage of diabetes development. 63 control subjects without any family history of diabetes and with normal glucose tolerance (NGT) and 74 healthy, first-degree relatives (FDRs) of type 2 diabetic patients were recruited in the study. All subjects underwent a 75 g oral glucose tolerance (OGTT) test after having fasted overnight. Plasma glucose, insulin, total cholesterol, HDL cholesterol, triglycerides, chemerin, and adiponectin were measured. FDR subjects had higher BMI, WHR, waist, fasting plasma glucose, fasting insulin, TG, UA, HOMA-IR, LDL-C, and lower HDL- C levels than control subjects (p < 0.05). The FDRs group had significantly lower adiponectin levels while chemerin was higher. Plasma chemerin levels were independently correlated with HOMA-IR, FINS, TG, FPG, and adiponectin level. Multiple stepwise regression analysis showed that HOMA-IR and TG were independent risk factors that influenced circulating chemerin levels. These findings showed a significant increase of chemerin levels in FDR subjects which suggested that chemerin may be involved in the development and progression of insulin resistance.