A novel mouse model of familial combined hyperlipidemia and atherosclerosis.

Within the context of residual cardiovascular risk in post-statin era, emerging evidence from epidemiologic and human genetic studies have demonstrated that triglyceride (TG)-rich lipoproteins and their remnants are causally related to cardiovascular risk. While, carriers of loss-of-function mutations of ApoC3 have low TG levels and are protected from cardiovascular disease (CVD). Of translational significance, siRNAs/antisense oligonucleotide (ASO) targeting ApoC3 is beneficial for patients with atherosclerotic CVD. Therefore, animal models of atherosclerosis with both hypercholesterolemia and hypertriglyceridemia are important for the discovery of novel therapeutic strategies targeting TG-lowering on top of traditional cholesterol-lowering. In this study, we constructed a novel mouse model of familial combined hyperlipidemia through inserting a human ApoC3 transgene (hApoC3-Tg) into C57BL/6 J mice and injecting a gain-of-function variant of adeno-associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9)-D377Y concurrently with high cholesterol diet (HCD) feeding for 16 weeks. In the last 10 weeks, hApoC3-Tg mice were orally treated with a combination of atorvastatin (10 mg·kg-1·d-1) and fenofibrate (100 mg·kg-1·d-1). HCD-treated hApoC3-Tg mice demonstrated elevated levels of serum TG, total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C). Oral administration of atorvastatin and fenofibrate significantly decreased the plaque sizes of en face aorta, aortic sinus and innominate artery accompanied by improved lipid profile and distribution. In summary, this novel mouse model is of considerable clinical relevance for evaluation of anti-atherosclerotic drugs by targeting both hypercholesterolemia and hypertriglyceridemia.

The clinical utility of polygenic risk scores for combined hyperlipidemia.

PURPOSE OF REVIEW: Combined hyperlipidemia is the most common lipid disorder and is strongly polygenic. Given its prevalence and associated risk for atherosclerotic cardiovascular disease, this review describes the potential for utilizing polygenic risk scores for risk prediction and management of combined hyperlipidemia. RECENT FINDINGS: Different diagnostic criteria have led to inconsistent prevalence estimates and missed diagnoses. Given that individuals with combined hyperlipidemia have risk estimates for incident coronary artery disease similar to individuals with familial hypercholesterolemia, early identification and therapeutic management of those affected is crucial. With diagnostic criteria including traits such apolipoprotein B, low-density lipoprotein cholesterol, and triglyceride, polygenic risk scores for these traits strongly associate with combined hyperlipidemia and could be used in combination for clinical risk prediction models and developing specific treatment plans for patients. SUMMARY: Polygenic risk scores are effective tools in risk prediction of combined hyperlipidemia, can provide insight into disease pathophysiology, and may be useful in managing and guiding treatment plans for patients. However, efforts to ensure equitable polygenic risk score performance across different genetic ancestry groups is necessary before clinical implementation in order to prevent the exacerbation of racial disparities in the clinic.

Familial combined hyperlipidemia is a polygenic trait.

PURPOSE OF REVIEW: : Familial combined hyperlipidemia (FCH), defined by concurrently elevated plasma triglyceride (TG) and low-density lipoprotein (LDL) cholesterol, has long been investigated to characterize its genetic basis. Despite almost half a century of searching, a single gene cause for the phenotype has not yet been identified. RECENT FINDINGS: : Recent studies using next-generation genetic analytic methods confirm that FCH has a polygenic basis, with a clear large contribution from the accumulation of small-to-moderate effect common single nucleotide polymorphisms (SNPs) throughout the genome that is associated with raising TG, and probably also those raising LDL cholesterol. On the other hand, rare monogenic variants, such as those causing familial hypercholesterolemia, play a negligible role, if any. Genetic profiling suggests that patients with FCH and hypertriglyceridemia share a strong polygenic basis and show a similar profile of multiple TG-raising common SNPs. SUMMARY: : Recent progress in genomics has shown that most if not all of the genetic susceptibility to FCH is polygenic in nature. Future research should include larger cohort studies, with wider ancestral diversity, ancestry-specific polygenic scores, and investigation of epigenetic and lifestyle factors to help further elucidate the causative agents at play in cases where the genetic etiology remains to be defined.

Applying biochemical and structural characterization of hydroxycinnamate catabolic enzymes from soil metagenome for lignin valorization strategies.

The biocatalytic production of fuels and chemicals from plant biomass represents an attractive alternative to fossil fuel-based refineries. In this context, the mining and characterization of novel biocatalysts can promote disruptive innovation opportunities in the field of lignocellulose conversion and valorization. In the present work, we conducted the biochemical and structural characterization of two novel hydroxycinnamic acid catabolic enzymes, isolated from a lignin-degrading microbial consortium, a feruloyl-CoA synthetase, and a feruloyl-CoA hydratase-lyase, named LM-FCS2 and LM-FCHL2, respectively. Besides establishing the homology model structures for novel FCS and FCHL members with unique characteristics, the enzymes presented interesting biochemical features: LM-FCS2 showed stability in alkaline pHs and was able to convert a wide array of p-hydroxycinnamic acids to their respective CoA-thioesters, including sinapic acid; LM-FCHL2 efficiently converted feruloyl-CoA and p-coumaroyl-CoA into vanillin and 4-hydroxybenzaldehyde, respectively, and could produce vanillin directly from ferulic acid. The coupled reaction of LM-FCS2 and LM-FCHL2 produced vanillin, not only from commercial ferulic acid but also from a crude lignocellulosic hydrolysate. Collectively, this work illuminates the structure and function of two critical enzymes involved in converting ferulic acid into high-value molecules, thus providing valuable concepts applied to the development of plant biomass biorefineries. KEY POINTS: • Comprehensive characterization of feruloyl-CoA synthetase from metagenomic origin. • Novel low-resolution structures of hydroxycinnamate catabolic enzymes. • Production of vanillin via enzymatic reaction using lignocellulosic hydrolysates.

Genetics of Familial Combined Hyperlipidemia (FCHL) Disorder: An Update.

Familial combined hyperlipidemia (FCHL) is one of the most common familial lipoprotein disorders of the lipoproteins, with a prevalence of 0.5% to 2% in different populations. About 10% of these patients suffer from cardiovascular disease and this number is increased by up to 11.3% in the young survivors of myocardial infarction and by 40% among all the survivors of myocardial infarction. Although initially thought to be that FCHL has an inheritance pattern of monogenic, the disease's etiology is still not fully understood and it appears that FCHL has a complex pattern related to genetic variants, environmental factors, and lifestyles. Two strategies have been used to identify its complex genetic background: candidate gene and the linkage approach, which have yielded an extensive list of genes associated with FCHL with a variable degree of scientific evidence. Until now, more than 30 different genetic variants have been identified related to FCHL. In this study, we aimed to review the individual genes that have been described in FCHL and how these genes and variants can be related to the current concept of metabolic pathways resulting in familial combined hyperlipidemia.

Translating genetic association of lipid levels for biological and clinical application.

PURPOSE OF REVIEW: This review focuses on the foundational evidence from the last two decades of lipid genetics research and describes the current status of data-driven approaches for transethnic GWAS, fine-mapping, transcriptome informed fine-mapping, and disease prediction. RECENT FINDINGS: Current lipid genetics research aims to understand the association mechanisms and clinical relevance of lipid loci as well as to capture population specific associations found in global ancestries. Recent genome-wide trans-ethnic association meta-analyses have identified 118 novel lipid loci reaching genome-wide significance. Gene-based burden tests of whole exome sequencing data have identified three genes-PCSK9, LDLR, and APOB-with significant rare variant burden associated with familial dyslipidemia. Transcriptome-wide association studies discovered five previously unreported lipid-associated loci. Additionally, the predictive power of genome-wide genetic risk scores amalgamating the polygenic determinants of lipid levels can potentially be used to increase the accuracy of coronary artery disease prediction. CONCLUSIONS: Lipids are one of the most successful group of traits in the era of genome-wide genetic discovery for identification of novel loci and plausible drug targets. However, a substantial fraction of lipid trait heritability remains unexplained. Further analysis of diverse ancestries and state of the art methods for association locus refinement could potentially reveal some of this missing heritability and increase the clinical application of the genomic association results.

Comparative assessment of LDL-C and VLDL-C estimation in familial combined hyperlipidemia using Sampson's, Martin's and Friedewald's equations.

BACKGROUND: Sampson et al. developed a novel method to estimate very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) in the setting of hypertriglyceridemia. Familial Combined Hyperlipidemia (FCHL) is a common primary dyslipidemia in which lipoprotein composition interferes with LDL-C estimation. This study aimed to evaluate performance of LDL-C using this new method (LDL-S) compared with LDL-C estimated by Friedewald's and Martin eq. (LDL-F, LDL-M) in FCHL. METHODS: Data were collected from 340 subjects with confirmed FCHL. Concordance for VLDL-C measured by ultracentrifugation and LDL-C estimated using these measures compared to Sampson's, Martin's and Friedewald's equations was performed using correlation coefficients, root mean squared error (RMSE) and bias. Also, concordance of misclassified metrics according to LDL-C (< 70 and < 100 mg/dL) and Apo B (< 80 and < 65 mg/dL) thresholds were assessed. RESULTS: Sampson's equation was more accurate (RMSE 11.21 mg/dL; R2 = 0.88) compared to Martin's (RMSE 13.15 mg/dL; R2 = 0.875) and the Friedewald's equation (RMSE 13.7 mg/dL; R2 = 0.869). When assessing performance according to LDL-C, Sampson's had highest correlation and lowest RMSE compared to other equations (RMSE 19.99 mg/dL; R2 = 0.840). Comparing performance strength across triglyceride levels, Sampson's showed consistently improved correlations compared to Martin's and Friedewald's formulas for increasing triglycerides and for the FCHL phenotype of mixed dyslipidemia. Sampson's also had improved concordance with treatment goals. CONCLUSIONS: In FCHL, VLDL-C and LDL-C estimation using Sampson's formula showed higher concordance with lipid targets assessed using VLDL-C obtained by ultracentrifugation compared with Friedewald's and Martin's equations. Implementation of Sampson's formula could improve treatment monitoring in FCHL.

Molecular mechanisms, prevalence, and molecular methods for familial combined hyperlipidemia disease: A review.

Familial combined hyperlipidemia (FCHL) is the most common genetic dyslipidemia disorder which is accompanied by increasing of triglyceride and cholesterol. This disorder is a complex genetic disease although it also has monogenic forms. The familial form has several criteria for diagnosis that can be distinguished of nonfamilial position. It has been shown that a variety of internal and external risk factors are involved in the pathogenesis of FCHL. Environmental factors and the genetic background also play an important role in the FCHL pathogenesis. Many mechanisms and pathways are involved in lipid metabolism (ie, dysfunctional adipose tissue, hepatic fat and very low-density lipoprotein overproduction, triglyceride-rich lipoproteins, and clearance of low-density lipoprotein particles) that could lead to FCHL. Individuals with a positive family history like those who have a positive family history of cardiovascular diseases are more predispositions for this disorder. To date several methods have been used to identify the genetic background of the FCHL. In the current review, we summarized the prevalence and the molecular mechanisms involved in the FCHL disease. Moreover, we highlighted the used molecular methods for determining the genes involved in the FCHL.

Familial combined hyperlipidemia: An overview of the underlying molecular mechanisms and therapeutic strategies.

Among different types of dyslipidemia, familial combined hyperlipidemia (FCHL) is the most common genetic disorder, which is characterized by at least two different forms of lipid abnormalities: hypercholesterolemia and hypertriglyceridemia. FCHL is an important cause of cardiovascular diseases. FCHL is a heterogeneous condition linked with some metabolic defects that are closely associated with FCHL. These metabolic features include dysfunctional adipose tissue, delayed clearance of triglyceride-rich lipoproteins, overproduction of very low-density lipoprotein and hepatic lipids, and defect in the clearance of low-density lipoprotein particles. There are also some genes associated with FCHL such as those affecting the metabolism and clearance of plasma lipoprotein particles. Due to the high prevalence of FCHL especially in cardiovascular patients, targeted treatment is ideal but this necessitates identification of the genetic background of patients. This review describes the metabolic pathways and associated genes that are implicated in FCHL pathogenesis. We also review existing and novel treatment options for FCHL. © 2019 IUBMB Life, 71(9):1221-1229, 2019.

The Contribution of GWAS Loci in Familial Dyslipidemias.

Familial combined hyperlipidemia (FCH) is a complex and common familial dyslipidemia characterized by elevated total cholesterol and/or triglyceride levels with over five-fold risk of coronary heart disease. The genetic architecture and contribution of rare Mendelian and common variants to FCH susceptibility is unknown. In 53 Finnish FCH families, we genotyped and imputed nine million variants in 715 family members with DNA available. We studied the enrichment of variants previously implicated with monogenic dyslipidemias and/or lipid levels in the general population by comparing allele frequencies between the FCH families and population samples. We also constructed weighted polygenic scores using 212 lipid-associated SNPs and estimated the relative contributions of Mendelian variants and polygenic scores to the risk of FCH in the families. We identified, across the whole allele frequency spectrum, an enrichment of variants known to elevate, and a deficiency of variants known to lower LDL-C and/or TG levels among both probands and affected FCH individuals. The score based on TG associated SNPs was particularly high among affected individuals compared to non-affected family members. Out of 234 affected FCH individuals across the families, seven (3%) carried Mendelian variants and 83 (35%) showed high accumulation of either known LDL-C or TG elevating variants by having either polygenic score over the 90th percentile in the population. The positive predictive value of high score was much higher for affected FCH individuals than for similar sporadic cases in the population. FCH is highly polygenic, supporting the hypothesis that variants across the whole allele frequency spectrum contribute to this complex familial trait. Polygenic SNP panels improve identification of individuals affected with FCH, but their clinical utility remains to be defined.

Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial.

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.

Relationship Between Total Serum Bilirubin Levels and Carotid and Femoral Atherosclerosis in Familial Dyslipidemia.

OBJECTIVE: Bilirubin is a potent antioxidant that has been inversely related to cardiovascular disease. There is little information on serum total bilirubin (TB) in relation to atherosclerosis in familial dyslipidemia. We assessed the association between TB and carotid and femoral atherosclerosis in this high-risk group. APPROACH AND RESULTS: We evaluated 464 individuals with familial dyslipidemia (56% men; median age, 48 years), 322 with familial hypercholesterolemia, and 142 with familial combined hyperlipidemia. Carotid and femoral arteries were imaged bilaterally with a standardized ultrasonographic protocol. Mean and maximum intima-media thickness and plaque presence (≥1.2 mm) and height were recorded. Cross-sectional associations between TB and atherosclerosis variables were investigated in multivariable-adjusted models, including lipid values and hypolipidemic drug use. Inflammatory markers (C-reactive protein, total leukocyte count, and lipoprotein[a]) were also determined. Increasing TB levels were associated with decreasing intima-media thickness of all carotid segments (P<0.05, all). TB also related to carotid plaque, present in 78% of individuals, and to plaque burden (≥3 plaques), with odds ratios (95% confidence interval) 0.59 (0.36-0.98) and 0.57 (0.34-0.96) for each increase of 0.5 mg in TB, respectively. Findings were confirmed in a validation cohort of 177 subjects with nonfamilial dyslipidemia. Only the familial combined hyperlipidemia group, with higher inflammation-related markers, showed an inverse association between TB and femoral plaque height (ß=-0.183; P=0.030). CONCLUSIONS: TB was inversely and independently associated with carotid plaque burden in familial and nonfamilial dyslipidemia. These findings support the use of TB as a biomarker of atherosclerosis in this high-risk group.

FAMILIAL COMBINED HYPERLIPIDEMIA: CURRENT KNOWLEDGE, PERSPECTIVES, AND CONTROVERSIES.

Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36).

[Familial combined hyperlipidemia - the most common genetic dyslipidemia in population and in patients with premature atherothrombotic cardiovascular disease]. / Familiární kombinovaná hyperlipidemie - nejcastejsí familiární dyslipidemie v bezné populaci i u pacientu s casným výskytem aterotrombotických kardiovaskulárních príhod.

Familial combined hyperlipidemia (FCH) is the most frequent genetic dyslipidemia (DLP) with high risk of early atherosclerosis manifestation. It is characterized by elevated both triglycerides 1.5 mmol/l and apolipoprotein B 1.2 g/l (hyper-TG/hyper-ApoB fenotype), with at least two affected family members. Despite the fact that plasmatic levels of total cholesterol and LDL-C are usually lower than in familial hypercholesterolemia and full expression of DLP in FCH occurs in adulthood, risk of premature manifestation of atherosclerosis is similar in both these familial DLP. It is probably due to the presence of other atherogenic lipid and non-lipid risk factors, such as increased levels of triglyceride rich lipoprotein remnants, presence of small dense LDL, reduction of HDL-C, presence of insulin resistance with impaired glucose homeostasis, hepatic steatosis, arterial hypertension, hyperuricemia and presence of increased markers of systemic inflammation. The term "familial" usually implicates a monogenic trait. However, FCH is almost always nonmendelian. According to recent knowledge FCH is mostly polygenic with variable presence of large effect mutations, accumulation of several small-effect polymorphisms and some environmental influences. Therefore, FCH is rather a syndrome with common clinical presentation but multigenic causes. The term "familial combined hyperlipidemia" is embedded in clinical practice and so it is not necessary to abandon it, as it nearly urges to examination of first degree relatives. This might help to identify a great number of risk subjects who deserve appropriate management.Key words: apolipoprotein B - familial combined hyperlipidemia - genetics - insulin resistance - premature atherosclerosis - triglycerides.

Metabolism and proteomics of large and small dense LDL in combined hyperlipidemia: effects of rosuvastatin.

Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.

Dynamics of human adipose lipid turnover in health and metabolic disease.

Adipose tissue mass is determined by the storage and removal of triglycerides in adipocytes. Little is known, however, about adipose lipid turnover in humans in health and pathology. To study this in vivo, here we determined lipid age by measuring (14)C derived from above ground nuclear bomb tests in adipocyte lipids. We report that during the average ten-year lifespan of human adipocytes, triglycerides are renewed six times. Lipid age is independent of adipocyte size, is very stable across a wide range of adult ages and does not differ between genders. Adipocyte lipid turnover, however, is strongly related to conditions with disturbed lipid metabolism. In obesity, triglyceride removal rate (lipolysis followed by oxidation) is decreased and the amount of triglycerides stored each year is increased. In contrast, both lipid removal and storage rates are decreased in non-obese patients diagnosed with the most common hereditary form of dyslipidaemia, familial combined hyperlipidaemia. Lipid removal rate is positively correlated with the capacity of adipocytes to break down triglycerides, as assessed through lipolysis, and is inversely related to insulin resistance. Our data support a mechanism in which adipocyte lipid storage and removal have different roles in health and pathology. High storage but low triglyceride removal promotes fat tissue accumulation and obesity. Reduction of both triglyceride storage and removal decreases lipid shunting through adipose tissue and thus promotes dyslipidaemia. We identify adipocyte lipid turnover as a novel target for prevention and treatment of metabolic disease.

Combined hyperlipidemia: familial but not (usually) monogenic.

PURPOSE OF REVIEW: Combined hyperlipidemia (CHL) is a complex phenotype that is commonly encountered clinically and is often associated with the expression of early heart disease. The affixed adjective 'familial' gives the impression that the trait is monogenic, like familial hypercholesterolemia. But despite significant efforts, genetic studies have yielded little evidence of single gene determinants of CHL. RECENT FINDINGS: Sophisticated linkage studies suggest that individual lipid components of the CHL phenotype - such as elevated LDL and triglyceride - each have several determinants that segregate independently in families. Furthermore, DNA sequencing shows that rare large-effect variants in genes such as LDL receptor (LDLR) and lipoprotein lipase are found in some CHL patients, explaining the elevated LDL cholesterol and triglyceride components, respectively. In addition, multiple common small-effect lipid-altering variants accumulate in an individual's genome, raising the LDL cholesterol and/or triglyceride components by multiple mechanisms. Finally, secondary factors, such as poor diet, obesity,fatty liver or diabetes further modulate the expression of the biochemically defined CHL phenotype. SUMMARY: Given the current state of genetic understanding, CHL may be best conceptualized as a syndrome with common clinical presentation but multigenic causes, similar to other common conditions such as type 2 diabetes.

Increased thioredoxin levels are related to insulin resistance in familial combined hyperlipidaemia.

BACKGROUND: Thioredoxins (TRX) are major cellular protein disulphide reductases that are critical for redox regulation. Oxidative stress and inflammation play promoting roles in the genesis and progression of atherosclerosis, but until now scarce data are available considering the influence of TRX activity in familial combined hyperlipidaemia (FCH). Since FCH is associated with high risk of cardiovascular disease, the objective of the present study was to assess oxidative stress status in FCH patients, and evaluate the influence of insulin resistance (IR). MATERIALS AND METHODS: A cohort of 35 control subjects and 35 non-related FCH patients were included, all of them nondiabetic, normotensive and nonsmokers. We measured lipid profile, glucose and insulin levels in plasma, and markers of oxidative stress and inflammation such as oxidized glutathione (GSSG), reduced glutathione (GSH) and TRX. RESULTS: Familial combined hyperlipidaemia subjects showed significantly higher levels of GSSG, GSSG/GSH ratio and TRX than controls. In addition, FCH individuals with IR showed the worst profile of oxidative stress status compared to controls and FCH patients without IR (P < 0·01). TRX levels correlated with higher insulin resistance. CONCLUSION: Familial combined hyperlipidaemia patients showed increased TRX levels. TRX was positively correlated with IR. These data could partially explain the increased risk of cardiovascular events in primary dyslipidemic patients.

Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population.

BACKGROUND: Familial combined hyperlipidemia (FCH) is a polygenic and multifactorial disease characterized by a variable phenotype showing increased levels of triglycerides and/or cholesterol. The aim of this study was to identify single nucleotides (SNPs) in lipid-related genes associated with FCH. METHODS AND RESULTS: Twenty SNPs in lipid-related genes were studied in 142 control subjects and 165 FCH patients after excluding patients with mutations in the LDLR gene and patients with the E2/E2 genotype of APOE. In particular, we studied the 9996G > A (rs2073658) and 11235C > T (rs3737787) variants in the Upstream Stimulatory Factor 1 gene (USF1), and the -1131T > C (rs662799) and S19W (rs3135506) variants in the Apolipoprotein A-V gene (APOA5). We found that the frequencies of these variants differed between patients and controls and that are associated with different lipid profiles. At multivariate logistic regression SNP S19W in APOA5 remained significantly associated with FCH independently of age, sex, BMI, cholesterol and triglycerides. CONCLUSIONS: Our results show that the USF1 and APOA5 polymorphisms are associated with FCH and that the S19W SNP in the APOA5 gene is associated to the disease independently of total cholesterol, triglycerides and BMI. However, more extensive studies including other SNPs such as rs2516839 in USF1, are required.