Plasma Triglyceride Response Research Articles

Revisiting multi-omics-based predictors of the plasma triglyceride response to an omega-3 fatty acid supplementation.

The aim of the present study was to identify the metabolomic signature of responders and non-responders to an omega-3 fatty acid (n-3 FA) supplementation, and to test the ability of a multi-omics classifier combining genomic, lipidomic, and metabolomic features to discriminate plasma triglyceride (TG) response phenotypes. A total of 208 participants of the Fatty Acid Sensor (FAS). Study took 5 g per day of fish oil, providing 1.9-2.2 g eicosapentaenoic acid (EPA) and 1.1 g docosahexaenoic (DHA) daily over a 6-week period, and were further divided into two subgroups: responders and non-responders, according to the change in plasma TG levels after the supplementation. Changes in plasma levels of 6 short-chain fatty acids (SCFA) and 25 bile acids (BA) during the intervention were compared between subgroups using a linear mixed model, and the impact of SCFAs and BAs on the TG response was tested in a mediation analysis. Genotyping was conducted using the Illumina Human Omni-5 Quad BeadChip. Mass spectrometry was used to quantify plasma TG and cholesterol esters levels, as well as plasma SCFA and BA levels. A classifier was developed and tested within the DIABLO framework, which implements a partial least squares-discriminant analysis to multi-omics analysis. Different classifiers were developed by combining data from genomics, lipidomics, and metabolomics. Plasma levels of none of the SCFAs or BAs measured before and after the n-3 FA supplementation were significantly different between responders and non-responders. SCFAs but not BAs were marginally relevant in the classification of plasma TG responses. A classifier built by adding plasma SCFAs and lipidomic layers to genomic data was able to even the accuracy of 85% shown by the genomic predictor alone. These results inform on the marginal relevance of SCFA and BA plasma levels as surrogate measures of gut microbiome in the assessment of the interindividual variability observed in the plasma TG response to an n-3 FA supplementation. Genomic data still represent the best predictor of plasma TG response, and the inclusion of metabolomic data added little to the ability to discriminate the plasma TG response phenotypes.

Update of a Genetic Risk Score Predictive of the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation in the FAS Study

A genetic risk score (GRS) predictive of the plasma triglyceride (TG) response to an omega-3 fatty acid (n-3 FA) supplementation has been previously developed in the Fatty Acid Sensor (FAS) Study. Recently, novel single nucleotide polymorphisms (SNPs) interacting with a fish oil supplementation and associated with plasma lipid levels have been identified in the UK Biobank. The aim of this study was to verify whether the addition of SNPs identified in the UK Biobank to the GRS built in the FAS Study improves its capacity to predict the plasma TG response to an n-3 FA supplementation. SNPs interacting with fish oil supplementation in the modulation of plasma lipid levels in the UK Biobank and associated with plasma TG levels have been genotyped in participants of the FAS Study (n = 141). Participants have been supplemented with 5 g fish oil/day for six weeks. Plasma TG concentrations were measured before and after the supplementation. Based on the initial GRS of 31 SNPs (GRS31), we computed three new GRSs by adding new SNPs identified in the UK Biobank: GRS32 (rs55707100), GRS38 (seven new SNPs specifically associated with plasma TG levels), and GRS46 (all 15 new SNPs associated with plasma lipid levels). The initial GRS31 explained 50.1% of the variance in plasma TG levels during the intervention, whereas GRS32, GRS38, and GRS46 explained 49.1%, 45.9%, and 45%, respectively. A significant impact on the probability of being classified as a responder or a nonresponder was found for each of the GRSs analyzed, but none of them outperformed the predictive capacity of GRS31 in any of the metrics analyzed, i.e., accuracy, area under the response operating curve (AUC-ROC), sensitivity, specificity and McFadden's pseudo R2. The addition of SNPs identified in the UK Biobank to the initial GRS31 did not significantly improve its capacity to predict the plasma TG response to an n-3 FA supplementation. Thus, GRS31 still remains the most precise tool so far by which to discriminate the individual responsiveness to n-3 FAs. Further studies are needed in the field to increase our knowledge of factors underlying the heterogeneity observed in the metabolic response to an n-3 FA supplementation.

Postprandial Lipid Response Following a High Fat Meal in Rats Adapted to Dietary Fiber

Rats were adapted to diets containing 5 g/100 g cellulose (CL), 5 g/100 g oat bran fiber (OB) or 5 g/100 g psyllium husk (Psy) for 4 wk. Following a 12-h fast, animals were either killed at 0 h (baseline) or fed 4.5 g of a test meal that provided 50% energy from fat, then killed at 1, 4 or 6 h postprandially. Fasting plasma and HDL cholesterol concentrations were lower in Psy-fed animals than in rats fed either CL or OB. Plasma triglycerides increased significantly from baseline (0 h) in all groups but did not differ among diet treatments. Increases in triglyceride content of the chylomicron/VLDL fraction occurred in the CL- and OB-fed groups and in the HDL fraction of the Psy-fed group during the postprandial period. In unfed animals the hepatic and intestinal levels of apolipoprotein A-IV mRNA were higher in the CL-fed group than in the groups fed OB and Psy. Apolipoprotein B mRNA was higher in the intestine of the OB-fed group than in the groups fed CL and Psy and had a significant gradient along the small intestine, increasing in the distal third. The results suggest that chronic consumption of fiber is less likely to modify the acute plasma triglyceride response to a fat-containing test meal than if a fiber supplement is incorporated into the meal.

Blood Lipid Responses to Diets Enriched with Cottonseed Oil Compared with Olive Oil in Adults with High Cholesterol in a Randomized Trial

BackgroundIncreasing unsaturated fat intake is beneficial for cardiovascular health, but the type of unsaturated fat to recommend remains equivocal. ObjectivesWe investigated the effects of an 8-week diet intervention that was rich in either cottonseed oil (CSO; PUFA rich) or olive oil (OO; MUFA rich) on blood lipids in hypercholesterolemic adults. MethodsForty-three men and women with hypercholesterolemia (53 ± 10 years; BMI, 27.6 ± 4.8 kg/m2) completed this randomized parallel clinical trial consisting of an 8-week partial outpatient feeding intervention. Participants were given meals and snacks accounting for ∼60% of their daily energy needs, with 30% of energy needs from either CSO (n = 21) or OO (n = 22). At pre- and postdiet intervention visits, participants consumed a high-SFA meal (35% of total energy needs; 70% of energy from fat). The primary outcomes of fasting cholesterol profiles and secondary outcomes of postprandial blood lipids and glycemic markers were assessed over a 5-hour period. ResultsThere were greater reductions from baseline to week 8 in fasting serum total cholesterol (TC; −17.0 ± 3.94 mg/dL compared with −2.18 ± 3.72 mg/dL, respectively; P = 0.008), LDL cholesterol (−19.7 ± 3.94 mg/dL compared with −5.72 ± 4.23 mg/dL, respectively; P = 0.018), non–HDL cholesterol (−20.8 mg/dL ± 4.00 compared with −6.61 ± 4.01 mg/dL, respectively; P = 0.014), and apoB (−11.8 mg/dL ± 2.37 compared with −3.10 ± 2.99 mg/dL, respectively; P = 0.05), in CSO compared with OO. There were also visit effects from baseline to week 8 for increases in HDL cholesterol (CSO, 56.5 ± 2.79 mg/dL to 60.2 ± 3.35 mg/dL, respectively; OO: 59.7 ± 2.63 mg/dL to 64.1 ± 2.24 mg/dL, respectively; P < 0.001), and decreases in the TC:HDL-cholesterol ratio (CSO, 4.30 ± 0.27 mg/dL to 3.78 ± 0.27 mg/dL, respectively; OO, 3.94 ± 0.16 mg/dL to 3.57 ± 0.11 mg/dL, respectively; P < 0.001), regardless of group assignment. In response to the high-SFA meal, there were differences in postprandial plasma glucose (P = 0.003) and triglyceride (P = 0.004) responses and a trend in nonesterified fatty acids (P = 0.11) between groups, showing protection in the postprandial state from an occasional high-SFA fat meal with CSO, but not OO, diet enrichment. ConclusionsCSO, but not OO, diet enrichment caused substantial improvements in fasting and postprandial blood lipids and postprandial glycemia in hypercholesterolemic adults. This trial was registered at clinicaltrials.gov as NCT04397055.

Clinical Practice Guidelines Using GRADE and AGREE II for the Impact of Genetic Variants on Plasma Lipid/Lipoprotein/Apolipoprotein Responsiveness to Omega-3 Fatty Acids.

BackgroundA recent systematic review, which used the GRADE methodology, concluded that there is strong evidence for two gene-diet associations related to omega-3 and plasma triglyceride (TG) responses. Systematic reviews can be used to inform the development of clinical practice guidelines (CPGs).ObjectiveTo provide guidance for clinical practice related to genetic testing for evaluating responsiveness to dietary/supplemental omega-3s and their impact on plasma lipids/lipoproteins/apolipoproteins.DesignUsing the results of the abovementioned systematic review, the first CPGs in nutrigenetics were developed using the established GRADE methodology and AGREE II approach.ResultsThree clinical practice recommendations were developed. Most gene-diet associations identified in the literature lack adequate scientific and clinical validity to warrant consideration for implementing in a practice setting. However, two gene-diet associations with strong evidence (GRADE quality: moderate and high) can be considered for implementation into clinical practice in certain cases: male APOE-E4 carriers (rs429358, rs7412) and TG changes in response to the omega-3 fatty acids eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) as well as a 31-SNP nutrigenetic risk score and TG changes in response to EPA+DHA among adults with overweight/obesity. Ethical and regulatory implications must be considered when providing APOE nutrigenetic tests given the well-established link between APOE genetic variation and Alzheimer's Disease.ConclusionMost of the evidence in this area is not ready for implementation into clinical practice primarily due to low scientific validity (low quality of evidence). However, the first CPGs in nutrigenetics have been developed for two nutrigenetic associations with strong scientific validity, related to dietary/supplemental omega-3 and TG responses.

Daily Step Count and Postprandial Fat Metabolism.

Two benefits of acute exercise are the next day's lowering of the postprandial plasma triglyceride response to a high-fat meal and increased fat oxidation. However, if activity levels (daily steps) are very low, these acute adaptations to exercise do not occur. This phenomenon has been termed "exercise resistance." This study sought to systematically reduce daily step number and identify the range of step counts that elicit "exercise resistance." Ten participants completed three, 5-d trials in a randomized, crossover design with differing levels of step reduction. After 2 d of controlled activity, participants completed 2 d of LOW, LIMITED, or NORMAL steps (2675 ± 314, 4759 ± 276, and 8481 ± 581 steps per day, respectively). Participants completed a 1-h bout of running on the evening of the second day. High-fat tolerance tests were performed on the next morning, and postprandial responses were compared. After LOW and LIMITED, postprandial incremental area under the curve (AUC) of plasma triglyceride was elevated 22%-23% compared with NORMAL (P < 0.05). Whole body fat oxidation was also significantly lower (16%-19%, P < 0.05, respectively) in LOW and LIMITED compared with NORMAL. No significant differences were found between LOW and LIMITED. Two days of step reduction to approximately 2500-5000 steps per day in young healthy individuals impairs the ability of an acute bout of exercise to increase fat oxidation and attenuate postprandial increases in plasma triglycerides. This suggests that "exercise resistance" occurs in individuals taking approximately 5000 or fewer steps per day, whereas 8500 steps per day protects against exercise resistance in fat metabolism. It seems that fat metabolism is influenced more by the inhibitory effects of inactivity than by the stimulating effects derived from 1 h of moderate-intensity running.

Genetic risk prediction of the plasma triglyceride response to independent supplementations with eicosapentaenoic and docosahexaenoic acids: the ComparED Study

BackgroundWe previously built a genetic risk score (GRS) highly predictive of the plasma triglyceride (TG) response to an omega-3 fatty acid (n-3 FA) supplementation from marine sources. The objective of the present study was to test the potential of this GRS to predict the plasma TG responsiveness to supplementation with either eicosapentaenoic (EPA) or docosahexaenoic (DHA) acids in the Comparing EPA to DHA (ComparED) Study.MethodsThe ComparED Study is a double-blind, controlled, crossover trial, with participants randomized to three supplemented phases of 10 weeks each: (1) 2.7 g/day of DHA, (2) 2.7 g/day of EPA, and (3) 3 g/day of corn oil (control), separated by 9-week washouts. The 31 SNPs used to build the previous GRS were genotyped in 122 participants of the ComparED Study using TaqMan technology. The GRS for each participant was computed by summing the number of rare alleles. Ordinal and binary logistic models, adjusted for age, sex, and body mass index, were used to calculate the ability of the GRS to predict TG responsiveness.ResultsThe GRS predicted TG responsiveness to EPA supplementation (p = 0.006), and a trend was observed for DHA supplementation (p = 0.08). The exclusion of participants with neutral TG responsiveness clarified the association patterns and the predictive capability of the GRS (EPA, p = 0.0003, DHA p = 0.01).ConclusionResults of the present study suggest that the constructed GRS is a good predictor of the plasma TG response to supplementation with either DHA or EPA.Trial registrationClinicalTrials.gov, NCT01810003. The study protocol was registered on March 4, 2013.

Hourly 4-s Sprints Prevent Impairment of Postprandial Fat Metabolism from Inactivity.

This study determined if the interruption of prolonged sitting (i.e., 8 h of inactivity) with hourly cycling sprints of only 4-s duration each (i.e., 4 s × 5 per hour × 8 h = 160 s·d SPRINTS) improves PPL. The 4-s sprints used an inertial load ergometer and were followed by 45 s of seated rest. Four men and four women participated in two trials. Interventions consisted of an 8-h period of sitting (SIT), or a trial with equal sitting time interrupted with five SPRINTS every hour. The morning after the interventions, PPL and fat oxidation were measured over a 6-h period. Plasma glucose, insulin, and triglyceride concentrations were measured bihourly and incremental area under the curve (AUC) was calculated. No differences (P > 0.05) between interventions were found for plasma insulin or glucose AUC. However, SPRINTS displayed a 31% (408 ± 119 vs 593 ± 88 mg·dL per 6 h; P = 0.009) decrease in plasma triglyceride incremental AUC and a 43% increase in whole-body fat oxidation (P = 0.001) when compared with SIT. These data indicate that hourly very short bouts (4 s) of maximal intensity cycle sprints interrupting prolonged sitting can significantly lower the next day's postprandial plasma triglyceride response and increase fat oxidation after a high-fat meal in healthy young adults. Given that these improvements were elicited from only 160 s of nonfatiguing exercise per day, it raises the question as to what is the least amount of exercise that can acutely improve fat metabolism and other aspects of health.

Genetic Risk Score Predictive of the Plasma Triglyceride Response to an Omega-3 Fatty Acid Supplementation in a Mexican Population.

Our group built a genetic risk score (GRS) of the plasma triglyceride (TG) response to an omega-3 (n-3) fatty acid (FA) supplementation in Caucasian Canadians that explained 21.53% of the TG variance. The objective was to refine the GRS by fine mapping and to test its association with the TG response in young Mexican adults. A total of 191 participants underwent a 6-week n-3 FA supplementation providing 2.7g/day of docosahexaenoic and eicosapentaenoic acids. Using quantitative polymerase chain reaction (PCR), 103 single-nucleotide polymorphisms (SNPs) were genotyped. A stepwise regression adjusted for age, sex, and body mass index (BMI) was used to select the strongest SNPs to include in the genetic risk model. A GRS was calculated from the sum of at-risk alleles. The contribution of the GRS to the TG response was assessed by ANCOVA with age, sex, and BMI included in the model. Several differences in allele frequency were observed between Canadians and Mexicans. Five lead SNPs were included in the genetic risk model, in which the GRS accounted for 11.01% of the variance of the TG response (p < 0.0001). These findings highlight the important contribution of genetic factors to the heterogeneity of the TG response to an n-3 FA supplementation among Mexicans.

Inactivity induces resistance to the metabolic benefits following acute exercise.

Acute exercise improves postprandial lipemia, glucose tolerance, and insulin sensitivity, all of which are risk factors for cardiovascular disease. However, recent research suggests that prolonged sedentary behavior might abolish these healthy metabolic benefits. Accordingly, this study aimed to elucidate the impact of an acute bout of exercise on postprandial plasma triglyceride, glucose, and insulin concentrations after 4 days of prolonged sitting (~13.5 h/day). Ten untrained to recreationally active men (n = 5) and women (n = 5) completed a counterbalanced, crossover study. Four days of prolonged sitting without exercise (SIT) were compared with 4 days of prolonged sitting with a 1-h bout of treadmill exercise (SIT + EX; 63.1 ± 5.2% V̇o2max) on the evening of the fourth day. The following morning, participants completed a high-fat/glucose tolerance test (HFGTT), during which plasma was collected over a 6-h period and analyzed for triglycerides, glucose, and insulin. No differences between trials (P > 0.05) were found in the overall plasma triglyceride, glucose, or insulin responses during the HFGTT. This lack of difference between trials comes with similarly low physical activity (~3,500-4,000 steps/day) on each day except for the 1-h bout of exercise during SIT + EX the day before the HFGTT. These data indicate that physical inactivity (e.g., sitting ~13.5 h/day and <4,000 steps/day) creates a condition whereby people become "resistant" to the metabolic improvements that are typically derived from an acute bout of aerobic exercise (i.e., exercise resistance). NEW & NOTEWORTHY In people who are physically inactive and sitting for a majority of the day, a 1-h bout of vigorous exercise failed to improve lipid, glucose, and insulin metabolism measured the next day. It seems that something inherent to inactivity and/or prolonged sitting makes the body resistant to the 1 h of exercise preventing the normally derived metabolic improvements following exercise.

Fine mapping of genome-wide association study signals to identify genetic markers of the plasma triglyceride response to an omega-3 fatty acid supplementation

Using a genome-wide association study (GWAS) approach, our group previously computed a genetic risk score (GRS) from single nucleotide polymorphisms (SNPs) of 10 loci that affect the plasma triglyceride (TG) response to an omega-3 (n-3) fatty acid (FA) supplementation. The objective was to compute a novel and more refined GRS using fine mapping to include a large number of genetic variants. A total of 208 participants of the Fatty Acid Sensor (FAS) Study received 5 g fish oil/d, containing 1.9-2.2 g eicosapentaenoic acid and 1.1 g docosahexanoic acid, for 6 wk. Plasma TG concentrations were measured before and after supplementation. Dense genotyping and genotype imputation were used to refine mapping around GWAS hits. A GRS was computed by summing the number of at-risk alleles of tagging SNPs. Analyses were replicated in samples of the FINGEN study. A total of 31 tagging SNPs associated with the TG response were used for GRS calculation in the FAS study. In a general linear model adjusted for age, sex, and body mass index, the GRS explained 49.73% of TG response variance (P<0.0001). Nonresponders to the n-3 FA supplementation had a higher GRS than did responders. In the FINGEN replication study, the GRS explained 3.67% of TG response variance (P=0.0006). Fine mapping proved to be effective to refine the previous GRS. Carrying increasing numbers of at-risk alleles of 31 SNPs confers a higher risk of being nonresponsive to n-3 FAs. The genetic profile therefore appears to be an important determinant of the plasma TG response to an n-3 FA supplementation and could be used to target those most likely to gain clinical benefit. This trial was registered at http://www.clinicaltrials.gov as NCT01343342.

Oral Glucose Mobilizes Triglyceride Stores From the HumanIntestine.

Background & AimsThe small intestine regulates plasma triglyceride (TG) concentration. Within enterocytes, dietary TGs are packaged into chylomicrons (CMs) for secretion or stored temporarily in cytoplasmic lipid droplets (CLDs) until further mobilization. We and others have shown that oral and intravenous glucose enhances CM particle secretion in human beings, however, the mechanisms through which this occurs are incompletely understood.MethodsTwo separate cohorts of participants ingested a high-fat liquid meal and, 5 hours later, were assigned randomly to ingest either a glucose solution or an equivalent volume of water. In 1 group (N = 6), plasma and lipoprotein TG responses were assessed in a randomized cross-over study. In a separate group (N = 24), duodenal biopsy specimens were obtained 1 hour after ingestion of glucose or water. Ultrastructural and proteomic analyses were performed on duodenal biopsy specimens.ResultsCompared with water, glucose ingestion increased circulating TGs within 30 minutes, mainly in the CM fraction. It decreased the total number of CLDs and the proportion of large-sized CLDs within enterocytes. We identified 2919 proteins in human duodenal tissue, 270 of which are related to lipid metabolism and 134 of which were differentially present in response to glucose compared with water ingestion.ConclusionsOral glucose mobilizes TGs stored within enterocyte CLDs to provide substrate for CM synthesis and secretion. Future studies elucidating the underlying signaling pathways may provide mechanistic insights that lead to the development of novel therapeutics for the treatment of hypertriglyceridemia.

Refinement of Genome-wide Association Study Shows New SLIT2 Polymorphisms Being Associated with the Plasma Triglyceride Response to Omega-3 Fatty Acids

Refinement of Genome-wide Association Study Shows New SLIT2 Polymorphisms Being Associated with the Plasma Triglyceride Response to Omega-3 Fatty Acids

Effects of Prior Aerobic Exercise and Prolonged Sitting on Postprandial Plasma Glucose and Triglyceride Responses

Effects of Prior Aerobic Exercise and Prolonged Sitting on Postprandial Plasma Glucose and Triglyceride Responses

ATP-citrate lyase: genetics, molecular biology and therapeutic target for dyslipidemia.

ATP-citrate lyase (ACLY) has re-emerged as a drug target for LDL cholesterol (LDL-C) lowering. We review ACLY as a therapeutic strategy, its genetics, its molecular and cellular biology, and also its inhibition. ACLY is a critical enzyme linking glucose catabolism to lipogenesis by providing acetyl-CoA from mitochondrial citrate for fatty acid and cholesterol biosynthesis. Human genetic variants have been associated with enhanced growth and survival of several cancers, and with attenuated plasma triglyceride responses to dietary fish oil. In mice, liver-specific Acly deficiency protects from hepatic steatosis and dyslipidemia, whereas adipose tissue-specific Acly deletion has no phenotype, supporting therapeutic inhibition of ACLY. A lipid-regulating compound, bempedoic acid, was discovered to potently inhibit ACLY, and in animal models, it prevents dyslipidemia and attenuates atherosclerosis. Phase 2 clinical trials revealed that bempedoic acid effectively lowers LDL-C as monotherapy, combined with ezetimibe, added to statin therapy and in statin-intolerant hypercholesterolemic patients. The efficacy of bempedoic acid as an LDL-C-lowering agent has validated ACLY inhibition as a therapeutic strategy. Positive results of phase 3 patient studies, together with long-term cardiovascular disease outcome trials, are required to establish ACLY as a major new target in cardiovascular medicine.

Effects of obesity on protein kinase C, brain creatine kinase, transcription, and autophagy in cochlea.

Diet-induced obesity (DIO) has been shown to exacerbate hearing degeneration via increased hypoxia, inflammatory responses, and cell loss via both caspase-dependent and caspase-independent apoptosis signaling pathways. This study aimed to investigate the effects of DIO on the mRNA expressions of protein kinase c-β (PKC-β), brain creatine kinase (CKB), transcription modification genes, and autophagy-related genes in the cochlea of CD/1 mice. Sixteen 4-week-old male CD/1 mice were randomly divided into 2 groups. For 16weeks, the DIO group was fed a high fat diet (60% kcal fat) and the controls were fed a standard diet. Morphometry, biochemistry, auditory brainstem response thresholds, omental fat, and histopathology of the cochlea were compared. Results showed that body weight, body length, body-mass index, omental fat, plasma triglyceride, and auditory brainstem response thresholds were significantly elevated in the DIO group compared with those of the control group. The ratio of vessel wall thickness to radius in the stria vascularis was significantly higher in the DIO group. The cell densities in the spiral ganglion, but not in the spiral prominence, of the cochlea were significantly lower in the DIO group. The expression of histone deacetylation gene 1 (HDAC1) was significantly higher in the DIO group than the control group. However, the expressions of PKC-β, CKB, HDAC3, histone acetyltransferase gene (P300), lysosome-associated membrane protein 2 (Lamp2), and light chain 3 (Lc3) genes were not significantly different between two groups. These results suggest that DIO might exacerbate hearing degeneration possibly via increased HDAC1 gene expression in the cochlea of CD/1 mice.

Plasma Triglyceride Levels May Be Modulated by Gene Expression of IQCJ, NXPH1, PHF17 and MYB in Humans.

A genome-wide association study (GWAS) by our group identified loci associated with the plasma triglyceride (TG) response to ω-3 fatty acid (FA) supplementation in IQCJ, NXPH1, PHF17 and MYB. Our aim is to investigate potential mechanisms underlying the associations between single nucleotide polymorphisms (SNPs) in the four genes and TG levels following ω-3 FA supplementation. 208 subjects received 3 g/day of ω-3 FA (1.9–2.2 g of EPA and 1.1 g of docosahexaenoic acid (DHA)) for six weeks. Plasma TG were measured before and after the intervention. 67 SNPs were selected to increase the density of markers near GWAS hits. Genome-wide expression and methylation analyses were conducted on respectively 30 and 35 participants’ blood sample together with in silico analyses. Two SNPs of IQCJ showed different affinities to splice sites depending on alleles. Expression levels were influenced by genotype for one SNP in NXPH1 and one in MYB. Associations between 12 tagged SNPs of IQCJ, 26 of NXPH1, seven of PHF17 and four of MYB and gene-specific CpG site methylation levels were found. The response of plasma TG to ω-3 FA supplementation may be modulated by the effect of DNA methylation on expression levels of genes revealed by GWAS.

Lomitapide for the treatment of hypertriglyceridemia

ABSTRACTIntroduction: Severe genetic forms of hypertriglyceridemia carry a risk of life-threatening pancreatitis and lack available effective treatments. Lomitapide is a microsomal triglyceride transfer protein inhibitor currently approved for treatment of homozygous familial hypercholesterolemia that may be useful in the management of severe hypertriglyceridemia.Areas covered: Published trials of lomitapide that reported plasma triglyceride response were reviewed, as was a case report of a patient with hypertriglyceridemia who was treated for 13 years with lomitapide. ClinicalTrials.gov was also reviewed for any unpublished results and ongoing trials.Expert opinion: Lomitapide demonstrates effective triglyceride lowering and may be a useful treatment for patients with genetic hypertriglyceridemia and recurrent acute pancreatitis who are refractory to traditional treatment. However, long term hepatic safety may be a concern and direct clinical trial-level data are lacking for this indication.

Statin-induced expression change of INSIG1 in lymphoblastoid cell lines correlates with plasma triglyceride statin response in a sex-specific manner

Statins are widely prescribed to lower plasma low-density lipoprotein (LDL) cholesterol levels. They also modestly reduce plasma triglyceride (TG), an independent cardiovascular disease risk factor, in most people. The mechanism and inter-individual variability of TG statin response is poorly understood. We measured statin-induced gene expression changes in lymphoblastoid cell lines derived from 150 participants of a simvastatin clinical trial and identified 23 genes (false discovery rate, FDR=15%) with expression changes correlated with plasma TG response. The correlation of insulin-induced gene 1 (INSIG1) expression changes with TG response (rho=0.32, q=0.11) was driven by men (interaction P=0.0055). rs73161338 was associated with INSIG1 expression changes (P=5.4 × 10−5) and TG response in two statin clinical trials (P=0.0048), predominantly in men. A combined model including INSIG1 expression level and splicing changes accounted for 29.5% of plasma TG statin response variance in men (P=5.6 × 10−6). Our results suggest that INSIG1 variation may contribute to statin-induced changes in plasma TG in a sex-specific manner.

Does the type of parenteral lipids matter? A clinical hint in critical illness

An altered lipid profile is common among intensive care unit (ICU) patients, but evidence regarding the impact of different fatty acid (FA) emulsions administered to patients requiring parenteral nutrition (PN) is scarce. This study aimed to compare the plasma triglycerides (TG) response to two types of commercial lipid emulsions: a structured mixture of long- and medium-chain triglycerides (LCT/MCT) or LCTs with n-9 FA (LCT+) in ICU patients. In this retrospective observational study conducted in a multidisciplinary ICU: two groups were defined by the type of emulsion used. Inclusion criteria were: consecutive patients on PN staying ≥4 days with one TG determination before commencing PN and at least one during PN. Recorded variables included energy intake, amount and type of nutritional lipids, propofol dose, glucose and protein intake, laboratory parameters, and all drugs received. Hypertriglyceridemia (hyperTG) was defined as TG >2mmol/L. The dynamic impact of the emulsion was analyzed in 187/757 patients completing the inclusion criteria (112 LCT/MCT and 75 LCT+). The demographic variables, severity indices, diagnostic categories, and outcomes did not differ between the two groups. Seventy-seven patients (41%) presented hyperTG. Both groups received similar daily energy (1604 versus 1511kcal/day), lipids (60 versus 61g/day), and glucose intake (233 versus 197g/day). There was no increase of TG concentration in those receiving the LCT/MCT emulsion compared to those receiving the LCT+ emulsion (0 and 0.2mmol/L, respectively, p<0.05). LCT/MCT emulsions are associated with a less pronounced increase of plasma TG levels than LCT+ emulsions.