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Aims Apolipoprotein B (APOB)-containing very LDL (VLDL) production, secretion, and clearance by hepatocytes is a central determinant of hepatic and circulating lipid levels. Impairment of any of the aforementioned processes is associated with the development of multiple diseases. Despite the discovery of genes and processes that govern hepatic VLDL metabolism, our understanding of the different mechanistic steps involved is far from complete. An impediment to these studies is the lack of tractable hepatocyte-based systems to interrogate and follow APOB in cells, which the current study addresses. Methods and results To facilitate the cellular study of VLDL metabolism, we generated human hepatic HepG2 and Huh-7 cell lines in which CRISPR/Cas9-based genome engineering was used to introduce the fluorescent protein mNeonGreen into the APOB gene locus. This results in the production of APOB100-mNeon that localizes predominantly to the endoplasmic reticulum (ER) and Golgi by immunofluorescence and electron microscopy imaging. The production and secretion of APOB100-mNeon can be quantitatively followed in medium over time and results in the production of lipoproteins that are taken up via the LDL receptor pathway. Importantly, the production and secretion of APOB-mNeon is sensitive to established pharmacological and physiological treatments and to genetic modifiers known to influence VLDL production in humans. As a showcase, we used HepG2-APOBmNeon cells to interrogate ER-associated degradation of APOB. The use of a dedicated sgRNA library targeting all established membrane-associated ER-resident E3 ubiquitin ligases led to the identification of SYNV1 as the E3 responsible for the degradation of poorly lipidated APOB in HepG2 cells. Conclusions In summary, the engineered cells reported here allow the study of hepatic VLDL assembly and secretion and facilitate spatiotemporal interrogation induced by pharmacologic and genetic perturbations. [ABSTRACT FROM AUTHOR]

Background: Aronia melanocarpa is a berry rich in polyphenols known for health benefits. However, the bioavailability of polyphenols has been questioned, and the individual taste acceptance of the fruit with its specific flavor varies. We recently observed substantial differences in the tolerability of aronia juice among healthy females, with half of the individuals tolerating aronia juice without complaints. Given the importance of the gut microbiome in food digestion, we investigated in this secondary analysis of the randomized placebo-controlled parallel intervention study (ClinicalTrials.gov registration: NCT05432362) if aronia juice tolerability was associated with changes in intestinal microbiota and bacterial metabolites, seeking for potential mechanistic insights into the impact on aronia polyphenol tolerance and metabolic outcomes. Results: Forty females were enrolled for this 6-week trial, receiving either 100 ml natural aronia juice (verum, V) twice daily or a polyphenol-free placebo (P) with a similar nutritional profile, followed by a 6-week washout. Within V, individuals were categorized into those who tolerated the juice well (Vt) or reported complaints (Vc). The gut microbiome diversity, as analyzed by 16S rRNA gene-based next-generation sequencing, remained unaltered in Vc but changed significantly in Vt. A MICOM-based flux balance analysis revealed pronounced differences in the 40 most predictive metabolites post-intervention. In Vc carbon-dioxide, ammonium and nine O-glycans were predicted due to a shift in microbial composition, while in Vt six bile acids were the most likely microbiota-derived metabolites. NMR metabolomics of plasma confirmed increased lipoprotein subclasses (LDL, VLDL) post-intervention, reverting after wash out. Stool samples maintained a stable metabolic profile. Conclusion: In linking aronia polyphenol tolerance to gut microbiota-derived metabolites, our study explores adaptive processes affecting lipoprotein profiles during high polyphenol ingestion in Vt and examines effects on mucosal gut health in response to intolerance to high polyphenol intake in Vc. Our results underpin the importance of individualized hormetic dosing for beneficial polyphenol effects, demonstrate dynamic gut microbiome responses to aronia juice, and emphasize personalized responses in polyphenol interventions. DsmAL-oYwbuhyB_vVwEdDj Video Abstract [ABSTRACT FROM AUTHOR]

Background: Asialoglycoprotein receptor 1 (ASGR1), primarily expressed on hepatocytes, promotes the clearance and the degradation of glycoproteins, including lipoproteins, from the circulation. In humans, loss-of-function variants of ASGR1 are associated with a favorable metabolic profile and reduced incidence of cardiovascular diseases. The molecular mechanisms by which ASGR1 could affect the onset of metabolic syndrome and obesity are unclear. Therefore, here we investigated the contribution of ASGR1 in the development of metabolic syndrome and obesity. Methods: ASGR1 deficient mice (ASGR1−/−) were subjected to a high-fat diet (45% Kcal from fat) for 20 weeks. The systemic metabolic profile, hepatic and visceral adipose tissue were characterized for metabolic and structural alterations, as well as for immune cells infiltration. Results: ASGR1−/− mice present a hypertrophic adipose tissue with 41% increase in fat accumulation in visceral adipose tissue (VAT), alongside with alteration in lipid metabolic pathways. Intriguingly, ASGR1−/− mice exhibit a comparable response to an acute glucose and insulin challenge in circulation, coupled with notably decreased in circulating cholesterol levels. Although the liver of ASGR1−/− have similar lipid accumulation to the WT mice, they present elevated levels of liver inflammation and a decrease in mitochondrial function. Conclusion: ASGR1 deficiency impacts energetic homeostasis during obesity leading to improved plasma lipid levels but increased VAT lipid accumulation and liver damage. [ABSTRACT FROM AUTHOR]

(1) Background: Previous studies have enriched high-density lipoproteins (HDL) using cholesteryl esters in rabbits with a three-quarter reduction in functional renal mass, suggesting that the kidneys participate in the cholesterol homeostasis of these lipoproteins. However, the possible role of the kidneys in lipoprotein metabolism is still controversial. To understand the role of the kidneys in regulating the HDL lipid content, we determined the turnover of HDL-cholesteryl esters in rabbits with a three-quarter renal mass reduction. (2) Methods: HDL subclass characterization was conducted, and the kinetics of plasma HDL-cholesteryl esters, labeled with tritium, were studied in rabbits with a 75% reduction in functional renal mass (Ntx). (3) Results: The reduced renal mass triggered the enrichment of cholesterol, specifically cholesteryl esters, in HDL subclasses. The exchange of cholesteryl esters between HDL and apo B-containing lipoproteins (VLDL/LDL) was not significantly modified in Ntx rabbits. Moreover, the cholesteryl esters of HDL and VLDL/LDL fluxes from the plasmatic compartment tended to decrease, but they only reached statistical significance when both fluxes were added to the Nxt group. Accordingly, the fractional catabolic rate (FCR) of the HDL-cholesteryl esters was lower in Ntx rabbits, concomitantly with its accumulation in HDL subclasses, probably because of the reduced mass of renal cells requiring this lipid from lipoproteins. [ABSTRACT FROM AUTHOR]

Ascophyllum nodosum, a brown algae abundantly found along the North Atlantic coast, is recognized for its high polysaccharide content. In this study, we investigated the anti-hyperlipidemic effect of fucoidans derived from A. nodosum, aiming to provide information for their potential application in anti-hyperlipidemic therapies and to explore comprehensive utilization of this Iceland brown seaweed. The crude fucoidan prepared from A. nodosum was separated using a diethylethanolamine column, resulting in two fucoidan fractions, AFC-1 and AFC-2. Both fractions were predominantly composed of fucose and xylose. AFC-1 exhibited a higher sulfate content of 27.8% compared to AFC-2 with 17.0%. AFC-2 was primarily sulfated at the hydroxy group of C2, whereas AFC-1 was sulfated at both the hydroxy groups of C2 and C4. To evaluate the anti-hyperlipidemic effect, a hyperlipidemia mouse model was established by feeding mice a high-fat diet. The effects of AFC-1, AFC-2, and the crude extract were investigated, with the drug atorvastatin used as a positive comparison. Among the different fucoidan fractions and doses, the high dose of AFC-2 administration demonstrated the most significant anti-hyperlipidemic effect across various aspects, including physiological parameters, blood glucose levels, lipid profile, histological analysis, and the activities of oxidative stress-related enzymes and lipoprotein-metabolism-related enzymes (p < 0.05 for the final body weight and p < 0.01 for the rest indicators, compared with the model group), and its effect is comparable to the atorvastatin administration. Furthermore, fucoidan administration resulted in a lower degree of loss in gut flora diversity compared to atorvastatin administration. These findings highlight the significant biomedical potential of fucoidans derived from A. nodosum as a promising therapeutic solution for hypolipidemia. [ABSTRACT FROM AUTHOR]

The involvement of cardiovascular disease in cancer onset and development represents a contemporary interest in basic science. It has been recognized, from the most recent research, that metabolic syndrome-related conditions, ranging from atherosclerosis to diabetes, elicit many pathways regulating lipid metabolism and lipid signaling that are also linked to the same framework of multiple potential mechanisms for inducing cancer. Otherwise, dyslipidemia and endothelial cell dysfunction in atherosclerosis may present common or even interdependent changes, similar to oncogenic molecules elevated in many forms of cancer. However, whether endothelial cell dysfunction in atherosclerotic disease provides signals that promote the pre-clinical onset and proliferation of malignant cells is an issue that requires further understanding, even though more questions are presented with every answer. Here, we highlight the molecular mechanisms that point to a causal link between lipid metabolism and glucose homeostasis in metabolic syndrome-related atherosclerotic disease with the development of cancer. The knowledge of these breakthrough mechanisms may pave the way for the application of new therapeutic targets and for implementing interventions in clinical practice. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (ApoE) is a member of apolipoprotein (apo) family and plays critical role in lipid metabolism. In this study, the relationship between abnormal lipid metabolism caused by ApoE-deficient and male reproduction was investigated. The effect of hyperbaric oxygen (HBO) therapy on 7-month-old ApoE-knockout male mice was assessed subsequently. Mice were randomly divided into 3 groups: control group (WT), ApoE (− / −) group (AP-CON), and ApoE (− / −) plus HBO group (AP-HBO), which received HBO treatment. We found that ApoE knockout caused a decrease in male reproductive capacity due to the reduced total sperm motility, progressive motility (PR), and lower blastocyst formation rate. HBO treatment could accelerate serum lipoprotein metabolism including LDL, T-CHO, and TG and semen quality. As a result, fertilization and blastocyst formation of AP-HBO group were higher than that of AP-CON, proving positive therapeutic effect. Mechanism exploration found that HBO treatment ameliorated the testicular microenvironment by attenuating inflammatory factor production and oxidative stress, eventually improved the sperm motility. Collectively, our study provided more evidences of HBO treatment for improving the semen quality of patients with abnormal lipid metabolism caused by ApoE-deficient. [ABSTRACT FROM AUTHOR]

Introduction: The bicuspid aortic valve (BAV) confers a high risk of ascending aorta dilatation (AAoD), although its progression seems highly variable. Furthermore, the implication of lipoprotein metabolism and inflammation in the mechanisms that underlie AAoD is not fully established. The aim of this study consisted of evaluating the impact of the lipoprotein and glycoprotein profiles in AAOD as well as its progression in BAV aortopathy. Methods: Using 1H-nuclear magnetic resonance (1H-NMR), we analyzed and compared the lipoprotein and glycoprotein profiles of plasma samples from 152 BAV patients with dilated and nondilated ascending aorta. Additionally, these profiles were also compared for 119 of these patients who were prospectively followed-up clinically and by echocardiography in the long-term (5 years). Ascending aorta dilation velocity (mm/year) was calculated for this analysis. Results: Several parameters related to the lipoprotein profile including remnant cholesterol, small LDL and IDL-cholesterol were found to be significantly increased in the dilated group compared to those in the nondilated group. The glycoprotein A-nuclear magnetic resonance (NMR) signal, a novel inflammation biomarker, was also observed to be increased in the dilated group. After performing multivariate analysis, remnant cholesterol remained an independent variable related to AAoD. In the long-term follow-up, proatherogenic lipoprotein parameters were related to ascending aorta dilatation velocity ascending. After a lineal regression analysis, non-HDL particles remained as an independent predictor of ascending aorta dilation velocity. Conclusions: Patients with BAV and AAoD presented a more pro-atherogenic profile assessed by 1H-NMR, especially related to triglyceride-rich lipoproteins. This pro-atherogenic profile seems to contribute to the higher growth rate of ascending aorta diameter. [ABSTRACT FROM AUTHOR]

The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors characterised by central obesity, atherogenic dyslipidaemia, and changes in the circulating lipidome; the underlying mechanisms that lead to this lipid remodelling have only been partially elucidated. This study used an integrated "omics" approach (untargeted whole serum lipidomics, targeted proteomics, and lipoprotein lipidomics) to study lipoprotein remodelling and HDL composition in subjects with central obesity diagnosed with MetS (vs. controls). Compared with healthy subjects, MetS patients showed higher free fatty acids, diglycerides, phosphatidylcholines, and triglycerides, particularly those enriched in products of de novo lipogenesis. On the other hand, the "lysophosphatidylcholines to phosphatidylcholines" and "cholesteryl ester to free cholesterol" ratios were reduced, pointing to a lower activity of lecithin cholesterol acyltransferase (LCAT) in MetS; LCAT activity (directly measured and predicted by lipidomic ratios) was positively correlated with high-density lipoprotein cholesterol (HDL-C) and negatively correlated with body mass index (BMI) and insulin resistance. Moreover, many phosphatidylcholines and sphingomyelins were significantly lower in the HDL of MetS patients and strongly correlated with BMI and clinical metabolic parameters. These results suggest that MetS is associated with an impairment of phospholipid metabolism in HDL, partially led by LCAT, and associated with obesity and underlying insulin resistance. This study proposes a candidate strategy to use integrated "omics" approaches to gain mechanistic insights into lipoprotein remodelling, thus deepening the knowledge regarding the molecular basis of the association between MetS and atherosclerosis. [ABSTRACT FROM AUTHOR]

Aims  Fibroblast growth factor (FGF) 21, a key regulator of energy metabolism, is currently evaluated in humans for treatment of type 2 diabetes and non-alcoholic steatohepatitis. However, the effects of FGF21 on cardiovascular benefit, particularly on lipoprotein metabolism in relation to atherogenesis, remain elusive. Methods and results   Here, the role of FGF21 in lipoprotein metabolism in relation to atherosclerosis development was investigated by pharmacological administration of a half-life extended recombinant FGF21 protein to hypercholesterolaemic APOE*3-Leiden.CETP mice, a well-established model mimicking atherosclerosis initiation and development in humans. FGF21 reduced plasma total cholesterol, explained by a reduction in non-HDL-cholesterol. Mechanistically, FGF21 promoted brown adipose tissue (BAT) activation and white adipose tissue (WAT) browning, thereby enhancing the selective uptake of fatty acids from triglyceride-rich lipoproteins into BAT and into browned WAT, consequently accelerating the clearance of the cholesterol-enriched remnants by the liver. In addition, FGF21 reduced body fat, ameliorated glucose tolerance and markedly reduced hepatic steatosis, related to up-regulated hepatic expression of genes involved in fatty acid oxidation and increased hepatic VLDL-triglyceride secretion. Ultimately, FGF21 largely decreased atherosclerotic lesion area, which was mainly explained by the reduction in non-HDL-cholesterol as shown by linear regression analysis, decreased lesion severity, and increased atherosclerotic plaque stability index. Conclusion  FGF21 improves hypercholesterolaemia by accelerating triglyceride-rich lipoprotein turnover as a result of activating BAT and browning of WAT, thereby reducing atherosclerotic lesion severity and increasing atherosclerotic lesion stability index. We have thus provided additional support for the clinical use of FGF21 in the treatment of atherosclerotic cardiovascular disease. [ABSTRACT FROM AUTHOR]

Obesity is associated with dyslipidemia, ectopic lipid deposition, and insulin resistance. In mice, the global or adipose-specific loss of function of the protein angiopoietin-like 4 (ANGPTL4) leads to decreased plasma triglyceride levels, enhanced adipose triglyceride uptake, and protection from high-fat diet (HFD)--induced glucose intolerance. ANGPTL4 is also expressed highly in the liver, but the role of liver-derived ANGPTL4 is unclear. The goal of this study was to determine the contribution of hepatocyte ANGPTL4 to triglyceride and glucose homeostasis in mice during a high-fat diet challenge. We generated hepatocyte-specific ANGPTL4 deficient (Angptl4LivKO) mice, fed them a 60% kcal/fat diet (HFD) for 6mo and assessed triglyceride, liver, and glucose metabolic phenotypes. We also explored the effects of prolonged fasting on Angptl4LivKO mice. The loss of hepatocyte-derived ANGPTL4 led to no major changes in triglyceride partitioning or lipoprotein lipase activity compared with control mice. Interestingly, although there was no difference in fasting plasma triglyceride levels after a 6 h fast, after an 18-h fast, normal chow diet-fed Angptl4LivKO mice had lower triglyceride levels than control mice. On a HFD, Angptl4LivKO mice initially showed no difference in glucose tolerance and insulin sensitivity, but improved glucose tolerance emerged in these mice after 6mo on HFD. Our data suggest that hepatocyte ANGPTL4 does not directly regulate triglyceride partitioning, but that loss of liver-derived ANGPTL4 may be protective from HFD-induced glucose intolerance and influence plasma triglyceride (TG) metabolism during prolonged fasting. [ABSTRACT FROM AUTHOR]

Background & Aims: The lysosomal enzyme, cathepsin D (CTSD) has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH), a disease characterised by hepatic steatosis and inflammation. We have previously demonstrated that specific inhibition of the extracellular CTSD leads to improved metabolic features in Sprague-Dawley rats with steatosis. However, the individual roles of extracellular and intracellular CTSD in NASH are not yet known. In the current study, we evaluated the underlying mechanisms of extracellular and intracellular CTSD fractions in NASH-related metabolic inflammation using specific small-molecule inhibitors. Methods: Low-density lipoprotein receptor knock out (Ldlr-/-) mice were fed a high-fat, high cholesterol (HFC) diet for ten weeks to induce NASH. Further, to investigate the effects of CTSD inhibition, mice were injected either with an intracellular (GA-12) or extracellular (CTD-002) CTSD inhibitor or vehicle control at doses of 50 mg/kg body weight subcutaneously once in two days for ten weeks. Results: Ldlr-/- mice treated with extracellular CTSD inhibitor showed reduced hepatic lipid accumulation and an associated increase in faecal bile acid levels as compared to intracellular CTSD inhibitor-treated mice. Furthermore, in contrast to intracellular CTSD inhibition, extracellular CTSD inhibition switched the systemic immune status of the mice to an anti-inflammatory profile. In line, label-free mass spectrometry-based proteomics revealed that extra- and intracellular CTSD fractions modulate proteins belonging to distinct metabolic pathways. Conclusion: We have provided clinically translatable evidence that extracellular CTSD inhibition shows some beneficial metabolic and systemic inflammatory effects which are distinct from intracellular CTSD inhibition. Considering that intracellular CTSD inhibition is involved in essential physiological processes, specific inhibitors capable of blocking extracellular CTSD activity, can be promising and safe NASH drugs. [ABSTRACT FROM AUTHOR]

Purpose of Review: Non-coding RNAs (ncRNAs) including microRNAs (miRNAs) and circular RNAs (circRNAs) are pivotal regulators of mRNA and protein expression that critically contribute to cardiovascular pathophysiology. Although little is known about the origin and function of such ncRNAs, they have been suggested as promising biomarkers with powerful therapeutic value in cardiovascular disease (CVD). In this review, we summarize the most recent findings on ncRNAs biology and their implication on cholesterol homeostasis and lipoprotein metabolism that highlight novel therapeutic avenues for treating dyslipidemia and atherosclerosis. Recent Findings: Clinical and experimental studies have elucidated the underlying effects that specific miRNAs impose both directly and indirectly regulating circulating high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very low-density lipoprotein (VLDL) metabolism and cardiovascular risk. Some of these relevant miRNAs include miR-148a, miR-128-1, miR-483, miR-520d, miR-224, miR-30c, miR-122, miR-33, miR-144, and miR-34. circRNAs are known to participate in a variety of physiological and pathological processes due to their abundance in tissues and their stage-specific expression activation. Recent studies have proven that circRNAs may be considered targets of CVD as well. Some of these cirRNAs are circ-0092317, circ_0003546, circ_0028198, and cirFASN that have been suggested to be strongly involved in lipoprotein metabolism; however, their relevance in CVD is still unknown. Summary: MicroRNA and cirRNAs have been proposed as powerful therapeutic targets for treating cardiometabolic disorders including atherosclerosis. Here, we discuss the recent findings in the field of lipid and lipoprotein metabolism underscoring the novel mechanisms by which some of these ncRNAs influence lipoprotein metabolism and CVD. [ABSTRACT FROM AUTHOR]

Glycerol tri[3H]oleate and [14C]cholesteryl oleate double‐labeled triglyceride‐rich lipoprotein (TRL)‐like particles are a well‐established tool to trace the effect of lipid‐modulating interventions on TRL metabolism. The routine generation of these particles involves sonication of a lipid mixture and subsequent fractionation of resulting particles into populations of different average size through density gradient ultracentrifugation. Here, we describe a simplified and more time‐efficient procedure for preparing TRL‐like particles without the need of fractionation. The simplified procedure shortened the preparation of particles from over 4 h to less than 2 h and generated particles with a higher yield, although with a smaller average size and more heterogeneous size distribution. In C57Bl/6J mice housed at thermoneutrality (30°C), the two preparations showed highly comparable plasma clearance and organ distribution of glycerol tri[3H]oleate‐derived [3H]oleate and [14C]cholesteryl oleate, as measures of lipolysis and core remnant uptake, respectively. Upon a cold challenge (14°C), plasma clearance was accelerated due to enhanced uptake of glycerol tri[3H]oleate‐derived [3H]oleate by brown adipose tissue. The simplified procedure resulted in a modestly increased particle uptake by the spleen, while uptake by other organs was comparable between the two preparations. In conclusion, the simplified procedure accelerates the preparation of TRL‐like particles for tracing in vivo TRL metabolism. We anticipate that this time‐efficient procedure will be useful for incorporation of PET‐traceable lipids to obtain more insight into human lipoprotein metabolism. [ABSTRACT FROM AUTHOR]

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a convertase enzyme mostly produced by the liver. It is a key regulator of LDL metabolism because of its ability to enhance degradation of the LDL receptor. PCSK9 also regulates the metabolism of lipoprotein(a) [Lp(a)] and triglyceride-rich lipoproteins (TRLs). Its key role in modulating atherosclerotic cardiovascular disease (ASCVD) is supported by genetic studies and clinical outcome trials. Kinetic studies provide mechanistic insight into the role of PCSK9 in regulating the physiology and pathophysiology of plasma lipids and lipoproteins. Kinetic data have demonstrated that plasma PCSK9 concentration is inversely associated with the clearance of LDL in men. Gain-of-function mutations of PCSK9 markedly increase plasma LDL-cholesterol concentrations due to impaired LDL-apoB catabolism. Conversely, PCSK9 deficiency results in low LDL-cholesterol associated with enhanced LDL-apoB clearance. Inhibition of PCSK9 with monoclonal antibodies (such as evolocumab or alirocumab) lowers plasma LDL-cholesterol and apoB levels chiefly by upregulating the catabolism of LDL particles in healthy individuals. As monotherapy, PCSK9 inhibitor reduced Lp(a) concentrations by decreasing the production rate. However, as combination therapy, it reduced the plasma concentration of Lp(a) by increasing the fractional catabolism of Lp(a) particles. In statin-treated patients with high Lp(a), PCSK9 inhibition lowers plasma Lp(a) concentrations by accelerating the catabolism of Lp(a) particles. The effect of PCSK9 inhibition on TRL metabolism has been studied in healthy individuals and in patients with type 2 diabetes. These findings suggest that PCSK9 appears to play a less important role in TRL than LDL metabolism. Kinetic studies of PCSK9 inhibition therapy on lipoprotein metabolism in diverse high risk patient populations (such as familial hypercholesterolemia) and new therapeutic combination also merit further investigation. [ABSTRACT FROM AUTHOR]

Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARα pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4α signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health. [ABSTRACT FROM AUTHOR]

Carbohydrate response element-binding protein (ChREBP) plays an important role in the development of type 2 diabetes, dyslipidemia, and non-alcoholic fatty liver disease, as well as tumorigenesis. ChREBP is highly expressed in lipogenic organs, such as liver, intestine, and adipose tissue, in which it regulates the production of acetyl CoA from glucose by inducing Pklr and Acyl expression. It has recently been demonstrated that ChREBP plays a role in the conversion of gut microbiota-derived acetate to acetyl CoA by activating its target gene, Acss2 , in the liver. ChREBP regulates fatty acid synthesis, elongation, and desaturation by inducing Acc1 and Fasn , elongation of long-chain fatty acids family member 6 (encoded by Elovl6), and Scd1 expression, respectively. ChREBP also regulates the formation of very low-density lipoprotein by inducing the expression of Mtp. Furthermore, it plays a crucial role in peripheral lipid metabolism by inducin g Fgf21 expression, as well as that of Angptl3 and Angptl8 , which are known to reduce peripheral lipoprotein lipase activity. In addition, ChREBP is involved in the production of palmitic-acid-5-hydroxystearic-acid, which increases insulin sensitivity in adipose tissue. Curiously, ChREBP is indirectly involved in fatty acid β-oxidation and subsequent ketogenesis. Thus, ChREBP regulates whole-body lipid metabolism by controlling the transcription of lipogenic enzymes and liver-derived cytokines. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation that, if left untreated, can cause joint destruction and physical impairments. The inflammatory process is systematic, and it is associated with increased morbidity and mortality. Over the last years, mortality presents a decreasing trend; still, there is a high burden of cardiovascular disease (CVD) in RA that seems to be related to coronary atherosclerosis. Chronic inflammation, physical inactivity, and drugs used to treat RA are some of the reasons. Thus, the management of CVD risk is essential and involves the patient's stratification using distinct parameters that include assessment of the blood lipid profile. However, 'dyslipidemia' in RA patients follows a different pattern under the impact of inflammatory processes, while therapies that target the underlying disease change the levels of specific lipid components. In this review, we explore the relationship between blood lipids and inflammation in the so-called ΄lipid paradox΄ in RA, and we present the existing knowledge over the influence of antirheumatic drugs on the lipid profile of RA patients. [ABSTRACT FROM AUTHOR]

This study investigated how camp management and tourist activities affect body condition, adrenocortical function, lipid profiles and metabolic status in female tourist elephants. We compared twice monthly serum insulin, glucose, fructosamine, total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), and fecal glucocorticoid metabolite (FGM) concentrations to body condition scores (BCS) at five camps with different management styles (e.g., tourist activities, work type, diet) between the High (November–February) and Low (March–October) tourist seasons. There were significant camp effects on health parameters, with BCS, TC, HDL, insulin and glucose being among the highest, and G:I being the lowest (less heathy) in elephants at an observation camp compared to those at camps where elephants received exercise by providing rides to tourists. Differences between High and Low tourist season months also were found for all measures, except TG and FGM concentrations. Both work time and walking distance were negatively correlated to glucose, fructosamine and insulin, while walking distance was negatively related to FGM concentrations. By contrast, positive associations were found between tourist number and BCS, TG, and insulin, perhaps related to tourists feeding elephants. Quantity of supplementary diet items (e.g., bananas, sugar cane, pumpkin) were positively correlated with FGM concentrations, glucose, fructosamine, and insulin. This study provides evidence that body condition, adrenal activity, metabolic markers, and lipid profiles in captive elephants may be affected by visitor numbers, work activities, and the amount of supplementary foods offered by tourists. Some activities appear to have negative (e.g., feeding), while others (e.g., exercise) may have positive effects on health and welfare. We conclude that camps adopting a more hands-off approach to tourism need to ensure elephants remain healthy by providing environments that encourage activity and rely on more natural diets or foraging. [ABSTRACT FROM AUTHOR]

Borrelia burgdorferi, the causative agent of Lyme disease in humans, is maintained in a complex biphasic life cycle, which alternates between tick and vertebrate hosts. To successfully survive and complete its enzootic cycle, B. burgdorferi adapts to diverse hosts by regulating genes required for survival in specific environments. Here we describe the first ever use of transposon insertion sequencing (Tn-seq) to identify genes required for B. burgdorferi survival in its tick host. We found that insertions into 46 genes resulted in a complete loss of recovery of mutants from larval Ixodes ticks. Insertions in an additional 56 genes resulted in a >90% decrease in fitness. The screen identified both previously known and new genes important for larval tick survival. Almost half of the genes required for survival in the tick encode proteins of unknown function, while a significant portion (over 20%) encode membrane-associated proteins or lipoproteins. We validated the results of the screen for five Tn mutants by performing individual competition assays using mutant and complemented strains. To better understand the role of one of these genes in tick survival, we conducted mechanistic studies of bb0017, a gene previously shown to be required for resistance against oxidative stress. In this study we show that BB0017 affects the regulation of key borrelial virulence determinants. The application of Tn-seq to in vivo screening of B. burgdorferi in its natural vector is a powerful tool that can be used to address many different aspects of the host pathogen interaction. [ABSTRACT FROM AUTHOR]

Cardiovascular disease is the leading cause of death worldwide, and elevated lipid levels is a major contributor. Gene delivery, which involves controlled transfer of nucleic acids into cells and tissues, has been widely used in research to study lipid metabolism and physiology. Several technologies have been developed to somatically overexpress, silence, or disrupt genes in animal models and have greatly advanced our knowledge of metabolism. This is particularly true with regard to the liver, which plays a central role in lipoprotein metabolism and is amenable to many delivery approaches. In addition to basic science applications, many of these delivery technologies have potential as gene therapies for both common and rare lipid disorders. This review discusses three major gene delivery technologies used in lipid research-including adeno-associated viral vector overexpression, antisense oligonucleotides and small interfering RNAs, and the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 genome editing system-and examines their potential therapeutic applications. [ABSTRACT FROM AUTHOR]

The axis of apolipoprotein M (apoM) and sphingosine-1-phosphate (S1P) is of importance to plasma lipid levels, endothelial function, and development of atherosclerosis. Menopause is accompanied by dyslipidemia and an increased risk of atherosclerosis, which can be lowered by exercise training. The aim of this study was to explore if effects of menopause and training are paralleled by changes in the apoM/S1P axis. Healthy, late premenopausal [n = 38, age 49.2 (SD 2)] and recent postmenopausal [n = 37, age 53.3 (SD 3)] women from the Copenhagen Women Study participated in a 3-mo, aerobic high-intensity exercise intervention. Before training, plasma apoM was higher in postmenopausal [1.08 µmol/l (SD 0.2)] compared with premenopausal [0.82 µmol/l (SD 0.2)] women (P < 0.0001). Plasma S1P was similar in the two groups [0.44 µmol/l (SD 0.1) and 0.46 µmol/l (SD 0.1), respectively]. Thus, the pretraining S1P/apoM ratio was 26% lower in postmenopausal than premenopausal women (P < 0.0001). After the training program, plasma apoM increased from 0.82 µmol/l (SD 0.2) to 0.90 µmol/l (SD 0.3) in premenopausal women and from 1.08 µmol/l (SD 0.2) to 1.16 µmol/l (SD 0.3) in postmenopausal women (P < 0.05). Plasma S1P increased from 0.44 µmol/l (SD 0.1) to 0.47 µmol/l (SD 0.1) in premenopausal women and from 0.46 µmol/l (SD 0.1) to 0.48 µmol/l (SD 0.1) in postmenopausal women (P < 0.05). The results suggest that menopause is accompanied by higher plasma apoM but not S1P concentrations and that exercise training increases plasma apoM and S1P in healthy middle-aged women irrespective of menopausal status. NEW & NOTEWORTHY The apolipoprotein M/sphingosine-1-phosphate (apoM/S1P) complex is involved in maintaining a healthy endothelial barrier function. Our study is the first, to our knowledge, to show how menopause affects the apoM/S1P axis. The results suggest that menopause is accompanied by higher plasma apoM but not S1P concentrations. Second, to our knowledge the study is also the first to show that exercise training increases both apoM/S1P in women irrespective of menopausal status. [ABSTRACT FROM AUTHOR]

Abstract: In view of the interrelations between NO, Fe, and LDL in the cardiovascular system it appears interesting to find out, if the lipoprotein particles undergo the process of iron‐nitrosylation, commonly observed for other proteins and what is the biological fate of iron‐nitrosylated LDL particles. Iron‐nitrosylated LDL preparation containing Fe(NO)2 motif (DNICLDL) was obtained and characterized for the first time. In order to test its interactions with potential target cells, DNICLDL was administered to the hepatoma HepG2 cells. The effects were referred to those induced by native LDL (nLDL) and oxidized LDL (oxLDL) particles. DNICLDL administration considerably increased total iron content in the studied cell line, but did not influence the level of calcein‐chelatable ions. DNICLDL was found to be low toxic to cells. The study suggests that DNICLDL might be a potential transducer of iron. © 2017 BioFactors, 44(2):192–201, 2018 [ABSTRACT FROM AUTHOR]

Abstract: The distinct effects of the estrogen and progestin components of hormonal therapy on the metabolism of apolipoprotein (apo) B‐containing lipoproteins have not been studied. We enrolled eight healthy postmenopausal women in a placebo‐controlled, randomized, double‐blind crossover study. Each subject received placebo, conjugated equine estrogen (CEE, 0.625 mg/day) and CEE plus medroxyprogesterone acetate (MPA, 2.5 mg/day) for 8 weeks in a randomized order, with a 4‐week washout between phases. Main outcomes were the fractional catabolic rate (FCR) and production rate (PR) of apo B100 in triglyceride‐rich lipoproteins (TRL), intermediate‐density lipoproteins (IDL) and low ‐density lipoprotein (LDL) and of apo B48 in TRL. Compared to placebo, CEE increased TRL apo B100 PR (p = 0.04). CEE also increased LDL apo B100 FCR (p = 0.02), but this effect was offset by a significant increase in LDL apo B100 PR (p = 0.04). Adding MPA to CEE negated the CEE effects resulting in no significant changes in TRL apo B100 PR and LDL apo B100 FCR and PR relative to placebo. Relative to placebo, during CEE there was a trend toward a reduction in plasma apo B48 concentrations and PR (p = 0.07 and p = 0.12, respectively). Compared with CEE, CEE + MPA significantly increased TRL apo B48 FCR (p = 0.02) as well as apo B48 PR (p = 0.01), resulting in no significant changes in apo B48 concentration. Estrogen and progestin have independent and opposing effects on the metabolism of the atherogenic apo B100‐ and apo B48‐containing lipoproteins. [ABSTRACT FROM AUTHOR]

Dyslipidemia, characterized by elevation of plasma low density lipoprotein cholesterol (LDL-C), triglyceride (TG) and reduction of plasma high density lipoprotein cholesterol (HDL-C), has been verified as a causal risk factor for cardiovascular diseases (CVD), leading to a high mortality rate in general population. It is important to understand the molecular metabolism underlying dyslipidemia in order to reduce the risk and to develop effective therapeutic approaches against CVD. ANGPTL3 (human) or Angptl3 (mouse), one member of the angiopoietin-like protein (ANGPTL) family, has been identified as an important regulator of lipid metabolism by inhibiting LPL and EL activity. Results have demonstrated that inactivation of Angptl3 in mice could obviously reduce the level of TG, LDL-C and the atherosclerotic lesion size, leading to a lower risk for dyslipidemia and CVD. Additionally, in humans, carriers with homozygous LOF mutations in ANGPTL3 have lower plasma LDL-C, TG levels and lower risk of atherosclerosis compared to the non-carriers. Here, we collect the latest data and results, giving a new insight into the important role of ANGPTL3 in controlling lipoprotein metabolism. Finally, we introduce two update reports on the antisense oligonucleotide and monoclonal antibody-based inactivation of ANGPTL3 in human clinical trials, to identify that ANGPTL3 could be a novel and effective target for the treatment of dyslipidemia and CVD. [ABSTRACT FROM AUTHOR]

Background: The substitution of omega (ω)-6 (n-6) polyunsaturated fatty acids (PUFAs) for saturated fatty acids (SFAs) is advocated in cardiovascular disease prevention. The impact of this substitution on lipoprotein metabolism in subjects with dyslipidemia associated with insulin resistance (IR) remains unknown. Objective: In men with dyslipidemia and IR, we evaluated the impact of substituting ω-6 PUFAs for SFAs on the in vivo kinetics of apolipoprotein (apo) B-containing lipoproteins and on the intestinal expression of key genes involved in lipoprotein metabolism. Design: Dyslipidemic and IR men (n = 36) were recruited for this double-blind, randomized, crossover, controlled trial. Subjects consumed, in a random order, a fully controlled diet rich in SFAs (SFAs: 13.4% of energy; ω-6 PUFAs: 4.0%) and a fully controlled diet rich in ω-6 PUFAs (SFAs: 6.0%; ω-6 PUFAs: 11.3%) for periods of 4 wk, separated by a 4-wk washout period. At the end of each diet, the in vivo kinetics of apoB-containing lipoproteins were measured and the intestinal expression of key genes involved in lipoproteinmetabolism was quantified in duodenal biopsies taken from each participant. Results: The substitution of ω-6 PUFAs for SFAs had no impact on TRL apoB-48 fractional catabolic rate (Δ = -3.8%, P = 0.7) and production rate (Δ=+1.2%, P=0.9), although it downregulated the intestinal expression of the microsomal triglyceride transfer protein (Δ = -18.4%, P = 0.006) and apoB (Δ = -16.6%, P = 0.005). The substitution of ω-6 PUFAs for SFAs decreased the LDL apoB-100 pool size (Δ=-7.8%; P=0.005). This difference was attributed to a reduction in the LDL apoB-100 production rate after the substitution of ω-6 PUFAs for SFAs (Δ = -10.0%; P = 0.003). Conclusions: This study demonstrates that the substitution of dietary ω-6 PUFAs for SFAs decreases the production and number of LDL particles in men with dyslipidemia and IR. This trial was registered at clinicaltrials.gov as NCT01934543. [ABSTRACT FROM AUTHOR]

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a causal risk factor for coronary heart disease (CHD) and calcific aortic valve stenosis (CAVS). Genetic, epidemiological andin vitrodata provide strong evidence for a pathogenic role for Lp(a) in the progression of atherothrombotic disease. Despite these advancements and a race to develop new Lp(a) lowering therapies, there are still many unanswered and emerging questions about the metabolism and pathophysiology of Lp(a). New studies have drawn attention to Lp(a) as a contributor to novel pathogenic processes, yet the mechanisms underlying the contribution of Lp(a) to CVD remain enigmatic. New therapeutics show promise in lowering plasma Lp(a) levels, although the complete mechanisms of Lp(a) lowering are not fully understood. Specific agents targeted to apolipoprotein(a) (apo(a)), namely antisense oligonucleotide therapy, demonstrate potential to decrease Lp(a) to levels below the 30–50 mg/dL (75–150 nmol/L) CVD risk threshold. This therapeutic approach should aid in assessing the benefit of lowering Lp(a) in a clinical setting. [ABSTRACT FROM PUBLISHER]

The potential cause-effect relationship between uric acid plasma concentrations and HDL functionality remains elusive. Therefore, this study aimed to explore the effect of oxonic acid (OA)-induced hyperuricemia on the HDL size distribution, lipid content of HDL subclasses, and apo AI turnover, as well as HDL functionality in New Zealand white rabbits. Experimental animals received OA 750 mg/kg/day by oral gavage during 21 days. The HDL-apo AI fractional catabolic rate (FCR) was determined by exogenous labeling with I, and HDL subclasses were determined by sequential ultracentrifugation and PAGE. Paraoxonase-1 activity (PON-1) and the effect of HDL on relaxation of aorta rings in vitro were determined as an indication of HDL functionality. Oxonic acid induced a sixfold increase of uricemia (0.84 ± 0.06 vs. 5.24 ± 0.12 mg/dL, P < 0.001), and significant decreases of triglycerides and phospholipids of HDL subclasses, whereas HDL size distribution and HDL-cholesterol remained unchanged. In addition, HDL-apo AI FCR was significantly higher in hyperuricemic rabbits than in the control group (0.03697 ± 0.0038 vs. 0.02605 ± 0.0017 h respectively, P < 0.05). Such structural and metabolic changes were associated with lower levels of PON-1 activities and deleterious effects of HDL particles on endothelium-mediated vasodilation. In conclusion, hyperuricemia is associated with structural and metabolic modifications of HDL that result in impaired functionality of these lipoproteins. Our data strongly suggest that uric acid per se exerts deleterious effects on HDL that contribute to increase the risk of atherosclerosis. [ABSTRACT FROM AUTHOR]

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Background: Given the characteristic atherogenic dyslipidemia of south Indian population and crucial role of APOA1, APOC3, APOA4 and APOA5 genes clustered in 11q23.3 chromosomal region in regulating lipoprotein metabolism and cholesterol homeostasis, a large number of recently identified variants are to be explored for their role in regulating the serum lipid parameters among south Indians. Methods: Using fluidigm SNP genotyping platform, a prioritized set of 96 SNPs of the 11q23.3 chromosomal region were genotyped on 516 individuals from Hyderabad, India, and its vicinity and aged >45 years. Results: The linear regression analysis of the individual lipid traits viz., TC, LDLC, HDLC, VLDL and TG with each of the 78 SNPs that confirm to HWE and with minor allele frequency > 1%, suggests 23 of those to be significantly associated (p ≤ 0.05) with at least one of these quantitative traits. Most importantly, the variant rs632153 is involved in elevating TC, LDLC, TG and VLDLs and probably playing a crucial role in the manifestation of dyslipidemia. Additionally, another three SNPs rs633389, rs2187126 and rs1263163 are found risk conferring to dyslipidemia by elevating LDLC and TC levels in the present population. Further, the ROC (receiver operating curve) analysis for the risk scores and dyslipidemia status yielded a significant area under curve (AUC) = 0.675, suggesting high discriminative power of the risk variants towards the condition. The interaction analysis suggests rs10488699-rs2187126 pair of the BUD13 gene to confer significant risk (Interaction odds ratio = 14.38, P = 7.17 × 105) towards dyslipidemia by elevating the TC levels (γ = 37.13, p = 6.614 × 105). On the other hand, the interaction between variants of APOA1 gene and BUD13 and/or ZPR1 regulatory genes at this region are associated with elevated TG and VLDL. Conclusion: The variants at 11q23.3 chromosomal region seem to determine the quantitative lipid traits and in turn dyslipidemia in the population of Hyderabad. Particularly, the variants rs632153, rs633389, rs2187126 and rs1263163 might be risk conferring to dyslipidemia by elevating LDLC and TC levels, while the variants of APOC3 and APOA1 genes might be the genetic determinants of elevated triglycerides in the present population. [ABSTRACT FROM AUTHOR]

The purpose of this study was to compare components of cardiometabolic risk and health behaviors of 20 family caregivers of allogeneic hematopoietic stem cell transplant patients to those of age, gender, and race/ethnicity-matched controls. A prospective, repeated measures design was used to compare cardiometabolic risk and health behaviors in caregivers and controls at three time-points: pre-transplantation, discharge, and six weeks post-discharge. Measures included components of metabolic syndrome, Reynolds Risk Score, NMR serum lipoprotein particle analyses, and the Health-Promoting Lifestyle Profile II (HPLP-II). Mixed-model repeated measure analyses were used. There were no between or within group differences in LDL cholesterol, HDL cholesterol, and triglycerides. There was a significant interaction effect between time and role in large VLDL concentration (VLDL-P) (F (2, 76) = 4.36, p = .016), with the trajectory of large VLDL-P increasing over time in caregivers while remaining stable in controls. Within caregivers, VLDL particle size (VLDL-Z) was significantly larger at time-point three compared to time-points one (p = .015) and two (p = .048), and VLDL-Z was significantly larger in caregivers than in controls at time point three (p = .012). HPLP-II scores were lower in caregivers than controls at all time-points (p < .01). These findings suggest that caregiving may have a bigger impact on triglycerides than on other lipids, and it is through this pathway that caregivers may be at increased cardiometabolic risk. More sensitive measurement methods, such as NMR lipoprotein particle analyses, may be able to detect early changes in cardiometabolic risk. [ABSTRACT FROM AUTHOR]

There is strong evidence that inadequate physical activity (PA) leads to an increased risk of lifestyle-related diseases and premature mortality. Physical activity on prescription (PAP) is a method to increase the level of PA of patients in primary care, but needs further evaluation. The aim of this observational study was to explore the association between PAP-treatment and the PA level of patients with metabolic risk factors and the relationship between changes in the PA level and health outcomes at the 6 month follow-up. This study included 444 patients in primary care, aged 27–85 years (56% females), who were physically inactive with at least one component of metabolic syndrome. The PAP-treatment model included: individualized dialogue concerning PA, prescribed PA, and a structured follow-up. A total of 368 patients (83%) completed the 6 months of follow-up. Of these patients, 73% increased their PA level and 42% moved from an inadequate PA level to sufficient, according to public health recommendations. There were significant improvements (p≤ 0.05) in the following metabolic risk factors: body mass index, waist circumference, systolic blood pressure, fasting plasma glucose, cholesterol, and low density lipoprotein. There were also significant improvements regarding health-related quality of life, assessed by the Short Form 36, in: general health, vitality, social function, mental health, role limitation-physical/emotional, mental component summary, and physical component summary. Regression analysis showed a significant association between changes in the PA level and health outcomes. During the first 6-month period, the caregiver provided PAP support 1–2 times. This study indicates that an individual-based model of PAP-treatment has the potential to change people’s PA behavior with improved metabolic risk factors and self-reported quality of life at the 6 month follow-up. Thus, PAP seems to be feasible in a clinical primary care practice, with minimum effort from healthcare professionals. [ABSTRACT FROM AUTHOR]

Objective: ANGPTL7 is a member of the Angiopoietin-like (ANGPTL) protein family that is composed of eight proteins (1–8). Increasing evidence is associating ANGPTL proteins to obesity and insulin resistance. The biological role of ANGPTL7 is yet to be understood except for a recently proposed role in the pathophysiology of glaucoma. This study was designed to shed light on the function of ANGPTL7 in obesity and its modulation by physical exercise as well as its potential association with lipid profile. Methods: A total of 144 subjects were enrolled in this study and finished three months of physical exercise. The participants were classified based on their BMI, 82 subjects were non-obese and 62 obese. ANGPTL7 levels in plasma and adipose tissue were measured by ELISA, RT-PCR and immunohistochemistry. Results: In this study, we showed that ANGPTL7 level was increased in the plasma of obese subjects (1249.05± 130.39 pg/mL) as compared to non-obese (930.34 ± 87.27 pg/mL) (p-Value = 0.032). ANGPTL7 Gene and protein expression levels in adipose tissue also showed over two fold increase. Physical exercise reduced circulating level of ANGPTL7 in the obese subjects to 740.98± 127.18 pg/mL, (p-Value = 0.007). ANGPTL7 expression in adipose tissue was also reduced after exercise. Finally, ANGPTL7 circulating level showed significant association with TG level in the obese subjects (R2 = 0.183, p-Value = 0.03). Conclusion: In conclusion, our data shows for the first time that obesity increases the level of ANGPTL7 in both plasma and adipose tissue. Increased expression of ANGPTL7 might play a minor role in the regulation of TG level in obese subjects either directly or through interaction with other ANGPTL protein members. Physical exercise reduced the level of ANGPTL7 highlighting the potential for targeting this protein as a therapeutic target for regulating dyslipidemia. [ABSTRACT FROM AUTHOR]

Estrogen is a steroidal hormone involved in several physiological functions in the female body including regulation of serum lipid metabolism and breast cancer (BC). Estrogen actions on serum lipids mostly occur through its binding to intracellular Estrogen Receptor alpha (ERalpha) isoform, expressed in most of tissues. This gene (ESR1) exhibit many polymorphic sites (SNPs) located either on translated and non-translated regions that regulate ERalpha protein expression and function. This paper aimed to investigate the association of two intronic SNPs of ESR1 gene, namely c454-397T>C (PvuII) and c454-351A>G (XbaI) to alterations in serum levels of total cholesterol (T-chol), total lipid (TL), low density lipoprotein cholesterol (LDL), high density lipoprotein (HDL), and triglycerides (TG) in a cohort of post-menopausal women. In addition, we aimed to associate presence of these SNPs to development of BC along 5 years period. To do so, a group of healthy 499, highly miscigenated, post-menopausal Brazilian women, were carried using PCR-FRLP technique and further confirmed by automatic sequence analysis as well followed through 5 years for BC incidence. Measurements of serum lipid profile by standard commercial methods were carried individually whereas Dual Energy X-ray Absorciometry (DXA) measured Body Mass Indexes (BMI), Fat Mass (FM), Lean Body Mass (LBM), and Body Water Content (BWC). No effects of PvuII SNP on ESR1 gene were observed on patient´s serum T-chol, TL, LDL, HDL, and TG. However, c454-397T>C PvuII SNP is associated to lower body fat and higher levels of lean mass and body water and lower incidence of BC. On the other hand, statistically significant effect of XbaI c454-351A>G SNP on serum TG and TL levels. Patients homozygous for X allele were followed up from 2010–2015. They showed higher incidence of breast cancer (BC) when compared to either heterozygous and any P allele combination. Moreover, the increasing of TG and TL serum concentrations associated to SNP XbaI c454-351A>G on ESR1 gene is enhanced in both obese (higher BMI) and elder women. Taken together, these results suggested that XbaI c454-351A>G SNP is associated to changes in lipid profile, particularly in serum TG and TL, in this cohort of post-menopausal woman. Also, this paper shows another link between obesity and BC corroborating the current thesis that both diseases are interlinked. [ABSTRACT FROM AUTHOR]

Background & Aims A major challenge in the management of nonalcoholic fatty liver disease ( NAFLD) is to identify patients with nonalcoholic steatohepatitis ( NASH) and early liver fibrosis. The progression of NAFLD is accompanied by distinctive changes in very low density lipoprotein ( VLDL), a lipoprotein particle produced exclusively in the liver. Herein, we sought to determine the characteristics of VLDL profiles associated with NASH and liver fibrosis. Methods We evaluated VLDL profiles of 128 patients from a single centre NAFLD registry, and examined VLDL size, total and subclass VLDL concentrations in relation to NAFLD activity score ( NAS), steatohepatitis and liver fibrosis as determined by liver biopsy. Results A near linear relationship was observed between mean VLDL particle size and NAFLD activity score ( NAS). In multivariate models, VLDL particle size was significantly associated with both NAS and NASH, after adjustment for BMI and diabetes. A decrease in small VLDL particle concentration was associated with more advanced liver fibrosis. In receiver operative characteristic analyses, mean VLDL size performed similarly to cytokeratin 18 in predicting NASH, whereas small VLDL particle concentration had similar performance to NAFLD fibrosis score in predicting stage 2 or above liver fibrosis. Conclusions The increase in mean VLDL size in NASH and decrease in small VLDL particle concentration in liver fibrosis likely reflect changes in the number and state of hepatocytes associated with NASH and fibrosis. In addition to its value in risk stratification of cardiovascular diseases, circulating VLDL profile may provide information for the staging of NAFLD disease severity. [ABSTRACT FROM AUTHOR]

Background Experimental data suggest that apolipoprotein (apo) C- II and C- III regulate triglyceride-rich lipoprotein ( TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC- II and apoC- III concentrations and kinetics in women. Material and methods The kinetics of plasma apoC- II, apoC- III and very low-density lipoprotein ( VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m2). Results Plasma apoC- II and apoC- III concentrations were positively associated with the concentrations of plasma triglycerides, VLDL1- and VLDL2-apoB-100 and triglyceride (all P < 0·05). ApoC- II production rate ( PR) was positively associated with VLDL1-apoB-100 concentration, VLDL1 triglyceride concentration and VLDL1 triglyceride PR, while apoC- II fractional catabolic rate ( FCR) was positively associated with VLDL1 triglyceride FCR (all P < 0·05). No significant associations were observed between apoC- II and VLDL2 apoB-100 or triglyceride kinetics. ApoC- III PR, but not FCR, was positively associated with VLDL1 triglyceride, and VLDL2-apoB-100 and triglyceride concentrations (all P < 0·05). No significant associations were observed between apoC- III and VLDL-apoB-100 and triglyceride kinetics. In multivariable analysis, including homoeostasis model assessment score, menopausal status and obesity, apoC- II concentration was significantly associated with plasma triglyceride, VLDL1-apoB-100 and VLDL1 triglyceride concentrations and PR. Using the same multivariable analysis, apoC- III was significantly associated with plasma triglyceride and VLDL1- and VLDL2-apoB-100 and triglyceride concentrations and FCR. Conclusions In women, plasma apoC- II and apoC- III concentrations are regulated by their respective PR and are significant, independent determinants of the kinetics and plasma concentrations of TRLs. [ABSTRACT FROM AUTHOR]

The catabolism and structure of high-density lipoproteins (HDL) may be the determining factor of their atheroprotective properties. To better understand the role of the kidney in HDL catabolism, here we characterized HDL subclasses and the catabolic rates of apo A-I in a rabbit model of proteinuria. Proteinuria was induced by intravenous administration of doxorubicin in New Zealand white rabbits ( n = 10). HDL size and HDL subclass lipids were assessed by electrophoresis of the isolated lipoproteins. The catabolic rate of HDL-apo A-I was evaluated by exogenous radiolabelling with iodine-131. Doxorubicin induced significant proteinuria after 4 weeks (4.47 ± 0.55 vs. 0.30 ± 0.02 g/L of protein in urine, P < 0.001) associated with increased uremia, creatininemia, and cardiotoxicity. Large HDL2b augmented significantly during proteinuria, whereas small HDL3b and HDL3c decreased compared to basal conditions. HDL2b, HDL2a, and HDL3a subclasses were enriched with triacylglycerols in proteinuric animals as determined by the triacylglycerol-to-phospholipid ratio; the cholesterol content in HDL subclasses remained unchanged. The fractional catabolic rate (FCR) of [I]-apo A-I in the proteinuric rabbits was faster (FCR = 0.036 h) compared to control rabbits group (FCR = 0.026 h, P < 0.05). Apo E increased and apo A-I decreased in HDL, whereas PON-1 activity increased in proteinuric rabbits. Proteinuria was associated with an increased number of large HDL2b particles and a decreased number of small HDL3b and 3c. Proteinuria was also connected to an alteration in HDL subclass lipids, apolipoprotein content of HDL, high paraoxonase-1 activity, and a rise in the fractional catabolic rate of the [I]-apo A-I. [ABSTRACT FROM AUTHOR]

The concept of lipoprotein mimetics was developed and extensively tested in the last three decades. Most lipoprotein mimetics were designed to recreate one or several functions of high-density lipoprotein (HDL) in the context of cardiovascular disease; however, the application of this approach is much broader. Lipoprotein mimetics should not just be seen as a set of compounds aimed at replenishing a deficiency or dysfunctionality of individual elements of lipoproteinmetabolism but rather as a designer concept with remarkable flexibility and numerous applications in medicine and biology. In the present review, we discuss the fundamental design principles used to create lipoprotein mimetics, mechanisms of their action, medical indications and efficacy in animal models and human studies. [ABSTRACT FROM AUTHOR]

Low density lipoprotein receptor (LDLR) plays an important role in plasma lipoprotein metabolism and pharmacological responses. Although mutations of LDLR and their functional associations with plasma LDL cholesterol concentrations have been described, no comprehensive comparisons of LDLR variants among populations are established. The aim of this study is to define the distribution of single nucleotide polymorphisms (SNPs) of LDLR and to discover novel variants across population groups. A total of 288 DNAs from 96 Korean, 48 Chinese, 48 Japanese, 48 African-American, and 48 European-American subjects were resequenced. A total of 59 SNPs (18 in the coding regions, 37 in the introns, and 4 in the 3′-untranslated region) were identified, including eight novel variants. Polymorphisms of LDLR showed significantly different distributions in comparisons among ethnic population groups ( P < 0.05, Fisher's exact test). Moreover, almost all of these differently distributed SNPs were common variants. Notably, prevalent variations-rs1003723, rs1799898, rs688, rs5925, rs6413504 in Europeans, nonsynonymous rs11669576 (Ala391Thr) in Africans, and rs14158 in Asians-were observed. In further in silico analyses for the novel SNPs, 2 intronic variants (+17716G>A in the intron 5 and +38569A>C in the intron 16) were predicted as potential branch point sites for alternative splicing. Although this study is not free from limitations such as insufficient sample size and no functional studies on the novel SNPs, our findings provides supporting information about LDLR genetic variability among ethnic groups and pharmacogenetics studies for plasma lipoprotein metabolism. [ABSTRACT FROM AUTHOR]

Apolipoprotein (Apo) D is an important protein produced in many parts of the body. It is necessary for the development and repair of the brain and protection from oxidative stress. The purpose of this study was to investigate the extent to which apoD interacts with lipoproteins in human plasma. By using detergent-free ELISA, we show that immobilized monoclonal antibodies against apoD very efficiently bind to low density lipoprotein (LDL) from plasma; this binding is as equally efficient as binding to an anti-apoB monoclonal antibody. Adding detergent to the plasma inhibited the binding, suggesting that the binding is dependent on the presence of intact lipoprotein particles. Reversing the system by using immobilized anti-apoB revealed that the affinity of apoD for LDL is rather low, suggesting that multiple bindings are needed for a durable connection. Biosensor experiments using purified lipoproteins also showed that purified apoD and high density lipoprotein 3 (HDL3), a lipoprotein fraction rich in apoD, were both able to bind LDL very efficiently, indicating that the HDL3-LDL interaction may be a physiological consequence of the affinity of apoD for LDL. Furthermore, we found that apoD increases the binding of HDL to actively growing T24 bladder carcinoma cells but not to quiescent, contact-inhibited, confluent T24 cells. This result is especially intriguing given that the T24 supernatant only contained detectable levels of apoD after growth inhibition, raising the possibility that alternating the expression of apoD and a putative apoD-receptor could give direction to the flow of lipids. In the current paper, we conclude that apoD mediates binding of HDL to LDL and to growing T24 carcinomas, thereby highlighting the importance of apoD in lipid metabolism. [ABSTRACT FROM AUTHOR]

Lipidomics reveals a remarkable diversity of lipids in human plasma. In this study, we have performed an in-depth lipidomic analysis of human plasma from healthy individuals and subjects with metabolic syndrome (MetS) in order to determine the lipidomic profile that allows prognosis of a pathological subpopulation with altered high-density lipoprotein (HDL) metabolism. The MetS population was categorized as having pathological or nonpathological HDL. Anthropometric parameters, cardiovascular risk markers, and lipoprotein subclasses of HDL and low-density lipoproteins were also evaluated. Lipidomic analysis revealed 357 differential molecules that were clustered ( k means) in the two groups. The molecules identified in the whole lipidome showed that MetS subjects presented lower levels of glycerolipids and higher levels of glycerophospholipids with respect to control subjects. In contrast, when only statistically differential lipids were taken into account, differences were found between the two groups in almost cases. Furthermore, levels of saturated fatty acids were higher in patients with pathological HDL levels than in controls, whereas levels of unsaturated fatty acids were lower. These results highlight the potential of lipidomics as a clinical tool for risk assessment and monitoring of disease. [ABSTRACT FROM AUTHOR]

Dietary cholesterol has received a lot of attention in regards to its potential association with both heart disease and Type 2 diabetes from health professionals and the general public. There is ample evidence from epidemiological data, meta-analysis reports and clinical interventions on the lack of a relationship between dietary cholesterol and heart disease risk. However, current reports appear to indicate that increased dietary cholesterol may be associated with an increased risk for heart disease in diabetic patients. Further, the relationship between dietary cholesterol and diabetes risk has not reached a consensus in the current literature and clinical studies have failed to prove that increased dietary cholesterol affects glucose metabolism or insulin resistance, indicating the need for more prospective and clinical studies. The current review will address the controversies from studies focusing on the associations and/or lack of correlation between dietary cholesterol and heart disease as well as dietary cholesterol and diabetes. [ABSTRACT FROM AUTHOR]

: Very low calorie diets (VLCD) with and without exercise programs lead to major metabolic improvements in obese type 2 diabetes patients. The mechanisms underlying these improvements have so far not been elucidated fully. To further investigate the mechanisms of a VLCD with or without exercise and to uncover possible biomarkers associated with these interventions, blood samples were collected from 27 obese type 2 diabetes patients before and after a 16-week VLCD (Modifast ∼450 kcal/day). Thirteen of these patients followed an exercise program in addition to the VCLD. Plasma was obtained from 27 lean and 27 obese controls as well. Proteomic analysis was performed using mass spectrometry (MS) and targeted multiple reaction monitoring (MRM) and a large scale isobaric tags for relative and absolute quantitation (iTRAQ) approach. After the 16-week VLCD, there was a significant decrease in body weight and HbA1c in all patients, without differences between the two intervention groups. Targeted MRM analysis revealed differences in several proteins, which could be divided in diabetes-associated (fibrinogen, transthyretin), obesity-associated (complement C3), and diet-associated markers (apolipoproteins, especially apolipoprotein A-IV). To further investigate the effects of exercise, large scale iTRAQ analysis was performed. However, no proteins were found showing an exercise effect. Thus, in this study, specific proteins were found to be differentially expressed in type 2 diabetes patients versus controls and before and after a VLCD. These proteins are potential disease state and intervention specific biomarkers. Trial Registration: Controlled-Trials.com [ABSTRACT FROM AUTHOR]

Background: Oxylipins mediate inflammation, vascular tension, and more. Their presence in lipoproteins could explain why lipoproteins mediate nearly identical activities. Methods: To determine how oxylipins are distributed in the lipoproteins of hypertriglyceridemic subjects, and whether omega-3 fatty acids alter them in a manner consistent with improved cardiovascular health, we recruited 15 dyslipidemic subjects whose levels of low density lipoprotein cholesterol (LDL-C) were at goal but who remained hypertriglyceridemic (200–499 mg/dL). They were treated them with the indicated dose of 4 g/d omega-3 acid ethyl esters (P-OM3) for 8 weeks. Measured oxylipins included mid-chain alcohols (HETEs, HEPEs and HDoHEs), ketones (KETEs), epoxides (as EpETrEs, EpETEs, and EpDPEs). Results: At baseline, arachidonate-oxylipins (HETEs, KETEs, and EpETrEs) were most abundant in plasma with the greatest fraction of total abundance (mean |95% CI|) being carried in high density lipoproteins (HDL); 42% |31, 57| followed by very low density lipoproteins (VLDL); 27% |20, 36|; and LDL 21% |16, 28|. EPA- and DHA-derived oxylipins constituted less than 11% of total. HDL carried alcohols and epoxides but VLDL was also rich in ketones. Treatment decreased AA-derived oxylipins across lipoprotein classes (−23% |−33, −12|, p = 0.0003), and expanded EPA−(322% |241, 422|, p<0.0001) and DHA-derived oxylipins (123% |80, 176|, p<0.0001). Conclusions: Each lipoprotein class carries a unique oxylipin complement. P-OM3 treatment alters the oxylipin content of all classes, reducing pro-inflammatory and increasing anti-inflammatory species, consistent with the improved inflammatory and vascular status associated with the treatment. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The development of metabolic syndrome is closely associated with the deregulation of lipid metabolism. Emerging evidence has demonstrated that microRNAs (miRNAs) are intensively engaged in lipid and lipoprotein metabolism by regulating genes involved in control of intracellular lipid synthesis, mitochondrial fatty acid oxidation, and lipoprotein assembly. Mitochondrial dysfunction induced by altered miRNA expression has been proposed to be a contributing factor in the onset of metabolic diseases, while at the same time, aberrant expression of certain miRNAs is associated with the induction of endoplasmic reticulum (ER) stress induced by nutrient-surplus. These studies position miRNAs as a link between oxidative stress and ER stress, two cellular stress pathways that are deregulated in metabolic disease and are associated with very-low-density lipoprotein (VLDL) overproduction. Dyslipoproteinemia frequently accompanied with metabolic syndrome is initiated largely by the overproduction of VLDL and altered biogenesis of high-density lipoprotein (HDL). In this review, we highlight recent findings on the regulatory impact of miRNAs on the metabolic homeostasis of mitochondria and ER as well as their contribution to the aberrant biogenesis of both VLDL and HDL in the context of metabolic disorders, in an attempt to gain further insights into the molecular mechanisms of dyslipidemia in the metabolic syndrome. [ABSTRACT FROM AUTHOR]

Aims Ectopic deposition of fat in skeletal muscle is a feature of metabolic syndrome, but its specific association with very-low-density lipoprotein ( VLDL)-apolipoprotein (apo) B-100 metabolism remains unclear. Methods We examined the association between skeletal muscle fat content and VLDL-apoB-100 kinetics in 25 obese subjects, and the responses of these variables to weight loss. The fat contents of liver, abdomen and skeletal muscle were determined by magnetic resonance imaging, and VLDL-apoB-100 kinetics were assessed using stable isotope tracers. Results In obese subjects who were insulin sensitive (homeostasis model assessment, HOMA, score ≤ 2.6, n = 12), skeletal muscle fat content was significantly associated with hepatic fat content (r = 0.636), energy intake (r = 0.694), plasma triglyceride (r = 0.644), apoB-100 (r = 0.529), glucose (r = 0.622), VLDL-apoB-100 concentrations (r = 0.860), VLDL-apoB-100 fractional catabolic rate ( FCR; r = −0.581) and VLDL-apoB-100 secretion rate (r = 0.607). These associations were not found in obese subjects who were insulin resistant ( HOMA score >2.6, n = 13). Of these 25 subjects, 10 obese subjects underwent a 16-week weight loss program. The low-fat diet achieved significant reduction (p < 0.05) in body weight, visceral and subcutaneous fat areas, liver and skeletal muscle fat, energy intake, triglyceride, insulin, HOMA score, VLDL-apoB100 concentrations and VLDL-apoB100 secretion rate. The percentage reduction of skeletal muscle fat with weight loss was significantly associated with the corresponding changes in VLDL-apoB100 concentration (r = 0.770, p = 0.009) and VLDL-apoB-100 secretion (r = 0.682, p = 0.030). Conclusions Skeletal muscle fat content is associated with VLDL-apoB-100 transport. Weight loss lowers skeletal muscle fat and VLDL-apoB-100 secretion. [ABSTRACT FROM AUTHOR]