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Accumulating evidence points to the causal role of triglyceride-rich lipoproteins and their cholesterol-enriched remnants in atherogenesis. Genetic studies in particular have not only revealed a relationship between plasma triglyceride levels and the risk of atherosclerotic cardiovascular disease, but have also identified key proteins responsible for the regulation of triglyceride transport. Kinetic studies in humans using stable isotope tracers have been especially useful in delineating the function of these proteins and revealing the hitherto unappreciated complexity of triglyceride-rich lipoprotein metabolism. Given that triglyceride is an essential energy source for mammals, triglyceride transport is regulated by numerous mechanisms that balance availability with the energy demands of the body. Ongoing investigations are focused on determining the consequences of dysregulation as a result of either dietary imprudence or genetic variation that increases the risk of atherosclerosis and pancreatitis. The identification of molecular control mechanisms involved in triglyceride metabolism has laid the groundwork for a ‘precision-medicine’ approach to therapy. Novel pharmacological agents under development have specific molecular targets within a regulatory framework, and their deployment heralds a new era in lipid-lowering-mediated prevention of disease. In this Review, we outline what is known about the dysregulation of triglyceride transport in human hypertriglyceridaemia.In this Review, Borén and colleagues provide an overview of the pathways involved in triglyceride-rich lipoprotein (TRL) assembly and intravascular processing, and discuss how the dysregulation of triglyceride transport can result in hypertriglyceridaemia.

Consumption of fructose, the sweetest of all naturally occurring carbohydrates, has increased dramatically in the last 40 years and is today commonly used commercially in soft drinks, juice, and baked goods. These products comprise a large proportion of the modern diet, in particular in children, adolescents, and young adults. A large body of evidence associate consumption of fructose and other sugar-sweetened beverages with insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia. In the long term, these risk factors may contribute to the development of type 2 diabetes and cardiovascular diseases. Fructose is absorbed in the small intestine and metabolized in the liver where it stimulates fructolysis, glycolysis, lipogenesis, and glucose production. This may result in hypertriglyceridemia and fatty liver. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important. Here we review recent evidence linking excessive fructose consumption to health risk markers and development of components of the Metabolic Syndrome.

Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids (SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy ( 1 H-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our 1 H-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity. Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Here, the authors use 1 H-MRS methodology to show hepatic SFA fraction is a measure of DNL and specifically may hamper hepatic insulin sensitivity.

To elucidate the molecular mechanisms underlying non‐alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome‐scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD + and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD + repletion on the development of NAFLD, we added precursors for GSH and NAD + biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof‐of‐concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment. Synopsis Personalized modeling and metabolic measurements identified altered GSH and NAD + metabolism as a prevailing feature in NAFLD. These findings suggested a potential treatment strategy for NAFLD patients based on increased oxidation of fat and increased synthesis of GSH. We developed personalized genome‐scale metabolic models for NAFLD patients. We found that altered GSH and NAD + metabolism is a prevailing feature in NAFLD. Plasma and liver levels of glycine and serine were lower in NAFLD patients. Supplementation of precursors for glutathione and NAD + decreased HS in mice. Serine supplementation decreased liver fat and improved markers of liver function in humans. Graphical Abstract Personalized modeling and metabolic measurements identified altered GSH and NAD + metabolism as a prevailing feature in NAFLD. These findings suggested a potential treatment strategy for NAFLD patients based on increased oxidation of fat and increased synthesis of GSH.

OBJECTIVE:--We explored whether cardiovascular disease (CVD) risk and the effects of fenofibrate differed in subjects with and without metabolic syndrome and according to various features of metabolic syndrome defined by the Adult Treatment Panel III (ATP III) in subjects with type 2 diabetes in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. RESEARCH DESIGN AND METHODS--The prevalence of metabolic syndrome and its features was calculated. Cox proportional models adjusted for age, sex, CVD status, and baseline A1C levels were used to determine the independent contributions of metabolic syndrome features to total CVD event rates and the effects of fenofibrate. RESULTS:--More than 80% of FIELD participants met the ATP III criteria for metabolic syndrome. Each ATP III feature of metabolic syndrome, apart from increased waist circumference, increased the absolute risk of CVD events over 5 years by at least 3%. Those with marked dyslipidemia (elevated triglycerides greater-than-or-equal2.3 mmol/l and low HDL cholesterol) were at the highest risk of CVD (17.8% over 5 years). Fenofibrate significantly reduced CVD events in those with low HDL cholesterol or hypertension. The largest effect of fenofibrate to reduce CVD risk was observed in subjects with marked dyslipidemia in whom a 27% relative risk reduction (95% CI 9-42, P = 0.005; number needed to treat = 23) was observed. Subjects with no prior CVD had greater risk reductions than the entire group. CONCLUSIONS:--Metabolic syndrome components identify higher CVD risk in individuals with type 2 diabetes, so the absolute benefits of fenofibrate are likely to be greater when metabolic syndrome features are present. The highest risk and greatest benefits of fenofibrate are seen among those with marked hypertriglyceridemia.

The prevalence of non‐alcoholic fatty liver disease (NAFLD) continues to increase dramatically, and there is no approved medication for its treatment. Recently, we predicted the underlying molecular mechanisms involved in the progression of NAFLD using network analysis and identified metabolic cofactors that might be beneficial as supplements to decrease human liver fat. Here, we first assessed the tolerability of the combined metabolic cofactors including l ‐serine, N ‐acetyl‐ l ‐cysteine (NAC), nicotinamide riboside (NR), and l ‐carnitine by performing a 7‐day rat toxicology study. Second, we performed a human calibration study by supplementing combined metabolic cofactors and a control study to study the kinetics of these metabolites in the plasma of healthy subjects with and without supplementation. We measured clinical parameters and observed no immediate side effects. Next, we generated plasma metabolomics and inflammatory protein markers data to reveal the acute changes associated with the supplementation of the metabolic cofactors. We also integrated metabolomics data using personalized genome‐scale metabolic modeling and observed that such supplementation significantly affects the global human lipid, amino acid, and antioxidant metabolism. Finally, we predicted blood concentrations of these compounds during daily long‐term supplementation by generating an ordinary differential equation model and liver concentrations of serine by generating a pharmacokinetic model and finally adjusted the doses of individual metabolic cofactors for future human clinical trials. Synopsis An animal toxicity study identifies changes in human plasma metabolome and inflammatory protein markers associated with the supplementation of metabolic cofactors. Global metabolic changes are identified by integrating this data using genome‐scale metabolic modelling. None of the administered doses of metabolic cofactors caused any detectable hematological, plasma chemistry or tissue effects in animals. The acute changes associated with the supplementation are analysed by plasma profiling in humans. Metabolic cofactor supplementation significantly affects the global human lipid, amino acid and anti‐oxidant metabolism. The doses of the individual metabolic cofactors are adjusted for future human clinical trials. Graphical Abstract An animal toxicity study identifies changes in human plasma metabolome and inflammatory protein markers associated with the supplementation of metabolic cofactors. Global metabolic changes are identified by integrating this data using genome‐scale metabolic modelling.

Previous research has shown that using population-specific reference panels has a significant effect on downstream population genomic analyses like haplotype phasing, genotype imputation, and association, especially in the context of population isolates. Here, we developed a high-resolution recombination rate mapping at 10 and 50 kb scale using high-coverage (20–30×) whole-genome sequenced data of 55 family trios from Finland and compared it to recombination rates of non-Finnish Europeans (NFE). We tested the downstream effects of the population-specific recombination rates in statistical phasing and genotype imputation in Finns as compared to the same analyses performed by using the NFE-based recombination rates. We found that Finnish recombination rates have a moderately high correlation (Spearman’s ρ = 0.67–0.79) with NFE, although on average (across all autosomal chromosomes), Finnish rates (2.268 ± 0.4209 cM/Mb) are 12–14% lower than NFE (2.641 ± 0.5032 cM/Mb). Finnish recombination map was found to have no significant effect in haplotype phasing accuracy (switch error rates ~2%) and average imputation concordance rates (97–98% for common, 92–96% for low frequency and 78–90% for rare variants). Our results suggest that haplotype phasing and genotype imputation mostly depend on population-specific contexts like appropriate reference panels and their sample size, but not on population-specific recombination maps. Even though recombination rate estimates had some differences between the Finnish and NFE populations, haplotyping and imputation had not been noticeably affected by the recombination map used. Therefore, the currently available HapMap recombination maps seem robust for population-specific phasing and imputation pipelines, even in the context of relatively isolated populations like Finland.

Association testing of multiple correlated phenotypes offers better power than univariate analysis of single traits. We analyzed 6,600 individuals from two population-based cohorts with both genome-wide SNP data and serum metabolomic profiles. From the observed correlation structure of 130 metabolites measured by nuclear magnetic resonance, we identified 11 metabolic networks and performed a multivariate genome-wide association analysis. We identified 34 genomic loci at genome-wide significance, of which 7 are novel. In comparison to univariate tests, multivariate association analysis identified nearly twice as many significant associations in total. Multi-tissue gene expression studies identified variants in our top loci, SERPINA1 and AQP9, as eQTLs and showed that SERPINA1 and AQP9 expression in human blood was associated with metabolites from their corresponding metabolic networks. Finally, liver expression of AQP9 was associated with atherosclerotic lesion area in mice, and in human arterial tissue both SERPINA1 and AQP9 were shown to be upregulated (6.3-fold and 4.6-fold, respectively) in atherosclerotic plaques. Our study illustrates the power of multi-phenotype GWAS and highlights candidate genes for atherosclerosis.

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid accumulation. The transmembrane 6 superfamily member 2 ( TM6SF2 ) E167K genetic variant associates with NAFLD and with reduced plasma triglyceride levels in humans. However, the molecular mechanisms underlying these associations remain unclear. We hypothesized that TM6SF2 E167K affects hepatic very low-density lipoprotein (VLDL) secretion and studied the kinetics of apolipoprotein B100 (apoB100) and triglyceride metabolism in VLDL in homozygous subjects. In 10 homozygote TM6SF2 E167K carriers and 10 matched controls, we employed stable-isotope tracer and compartmental modeling techniques to determine apoB100 and triglyceride kinetics in the 2 major VLDL subfractions: large triglyceride-rich VLDL 1 and smaller, less triglyceride-rich VLDL 2 . VLDL 1 -apoB100 production was markedly reduced in homozygote TM6SF2 E167K carriers compared with controls. Likewise, VLDL 1 -triglyceride production was 35% lower in the TM6SF2 E167K carriers. In contrast, the direct production rates for VLDL 2 -apoB100 and triglyceride were not different between carriers and controls. In conclusion, the TM6SF2 E167K genetic variant was linked to a specific reduction in hepatic secretion of large triglyceride-rich VLDL 1 . The impaired secretion of VLDL 1 explains the reduced plasma triglyceride concentration and provides a basis for understanding the lower risk of cardiovascular disease associated with the TM6SF2 E167K genetic variant.

To study the effect of exenatide on body composition and circulating cardiovascular risk biomarkers. Metformin-treated patients with type 2 diabetes (N = 69) were randomized to exenatide or insulin glargine and treated for 1 year. Body composition was evaluated by dual-energy X-ray absorptiometry. Additionally, body weight, waist circumference, and cardiovascular biomarkers were measured. Treatment with exenatide for 1 year significantly reduced body weight, waist circumference, and total body and trunkal fat mass by 6, 5, 11, and 13%, respectively. In addition, exenatide increased total adiponectin by 12% and reduced high-sensitivity C-reactive protein by 61%. Insulin glargine significantly reduced endothelin-1 by 7%. These changes were statistically independent of the change in total body fat mass and body weight. Exenatide treatment for 1 year reduced body fat mass and improved the profile of circulating biomarkers of cardiovascular risk. No significant changes were seen with insulin glargine except a trend for reduced endothelin-1 levels.