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Halocynthia aurantium is a marine organism that has been considered a promising source for bio-functional materials. Total lipids were extracted from H. aurantium tunic, and then they were separated into neutral lipids, glycolipids, and phospholipids. In the present study, fatty acid profiles of three lipids and their anti-inflammatory effects in RAW264.7 cells were investigated. Among the lipid classes, phospholipids showed the diversity of fatty acid constituents, compared with the glycolipids and neutral lipids. Three lipids contain different contents of fatty acids depending on the kinds of lipids. The most contents were saturated fatty acids (SFAs, 53–69% of the fatty acids) and monounsaturated fatty acids (MUFAs, 15–17% of fatty acids) and polyunsaturated fatty acids (PUFAs, 14–32% of fatty acids) are followed. H. aurantium lipids not only dose-dependently inhibited nitric oxide production but also reduced the expression of inflammatory cytokine genes such as TNF-α, IL-1β, and IL-6 in LPS-stimulated macrophages. It was also demonstrated that the expression of COX-2 was dose-dependently suppressed. Moreover, H. aurantium lipids decreased phosphorylation of NF-κB p-65, p38, ERK1/2, and JNK, suggesting that three lipids from H. aurantium tunic provide anti-inflammatory effects through NF-κB and MAPK signaling. These results indicate that H. aurantium is a potential source for anti-inflammation. [ABSTRACT FROM AUTHOR]

Background: The role of cholesterol levels in the development of atrial fibrillation (AF) is still controversial. In addition, whether and to what extent apolipoproteins are associated with the risk of AF is rarely studied. In this study, we aimed to investigate the association between blood lipid levels in midlife and subsequent risk of new-onset AF. Methods and findings: This population-based study included 65,136 individuals aged 45 to 60 years without overt cardiovascular diseases (CVDs) from the Swedish Apolipoprotein-Related Mortality Risk (AMORIS) cohort. Lipids were measured in 1985 to 1996, and individuals were followed until December 31, 2019 for incident AF (i.e., study outcome). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression, adjusting for age, sex, and socioeconomic status. Over a mean follow-up of 24.2 years (standard deviation 7.5, range 0.2 to 35.9), 13,871 (21.3%) incident AF cases occurred. Higher levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were statistically significantly associated with a lower risk of AF during the first 5 years of follow-up (HR = 0.61, 95% CI: 0.41 to 0.99, p = 0.013; HR = 0.64, 95% CI: 0.45 to 0.92, p = 0.016), but not thereafter (HR ranging from 0.94 [95% CI: 0.89 to 1.00, p = 0.038] to 0.96 [95% CI: 0.77 to 1.19, p > 0.05]). Lower levels of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) and higher triglycerides (TG)/HDL-C ratio were statistically significantly associated with a higher risk of AF during the entire follow-up (HR ranging from 1.13 [95% CI: 1.07 to 1.19, p < 0.001] to 1.53 [95% CI: 1.12 to 2.00, p = 0.007]). Apolipoprotein B (ApoB)/ApoA-I ratio was not associated with AF risk. The observed associations were similar among those who developed incident heart failure (HF)/coronary heart disease (CHD) and those who did not. The main limitations of this study include lack of adjustments for lifestyle factors and high blood pressure leading to potential residual confounding. Conclusions: High TC and LDL-C in midlife was associated with a lower risk of AF, but this association was present only within 5 years from lipid measurement and not thereafter. On the contrary, low HDL-C and ApoA-I and high TG/HDL-C ratio were associated with an increased risk of AF over almost 35 years of follow-up. ApoB/ApoA-I ratio was not associated with AF risk. Mozhu Ding and colleagues investigate investigate the association between blood lipid levels in midlife and subsequent risk of new-onset atrial fibrillation in Sweden. Author summary: Why was this study done?: High cholesterol level is an established risk factor for cardiovascular diseases (CVDs), such as coronary heart disease (CHD). However, the role of cholesterol levels in the development of atrial fibrillation (AF), a very common cardiac arrhythmia in older adults, is debated. Compared to cholesterols, apolipoprotein B (ApoB), apolipoprotein A-I (ApoA-I), and their ratios have been shown to better predict CVD, but whether and how they are associated with AF is unclear. What did the researchers do and find?: In this large Swedish cohort with blood-based biomarker information, 65,136 individuals free of overt CVD and aged 45 to 60 years at lipid measurement were followed for up to 35 years for new-onset AF. High levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) were associated with a lower risk of AF (hazard ratio, HR = 0.61, 95% confidence interval (CI): 0.41 to 0.99, p = 0.013; HR = 0.64, 95% CI: 0.45 to 0.92, p = 0.016), but this association was present only during the first 5 years since lipid measurement. On the contrary, low levels of high-density lipoprotein cholesterol (HDL-C) and ApoA-I and a high triglyceride (TG)/HDL-C ratio were associated with an increased risk of AF throughout the follow-up time (HR ranging from 1.13 [95% CI: 1.07 to 1.19, p < 0.001] to 1.53 [95% CI: 1.12 to 2.00, p = 0.007]). High ApoB/ApoA-I ratio was not associated with the risk of subsequent AF. What do these findings mean?: Dyslipidemia expressed by a high TC or LDL-C, or a poor atherogenic to anti-atherogenic balance, does not seem to be associated with an increased risk of developing AF. Instead, the findings suggest that metabolic syndrome and inflammation, as indicated by low HDL-C and ApoA-I and a high TG/HDL-C ratio, may play a role in the onset of AF. [ABSTRACT FROM AUTHOR]

Chronic hepatitis B virus (HBV) infection is characterized by the presence of high circulating levels of non-infectious lipoprotein-like HBV surface antigen (HBsAg) particles thought to contribute to chronic immune dysfunction in patients. Lipid and metabolomic analysis of humanized livers from immunodeficient chimeric mice (uPA/SCID) revealed that HBV infection dysregulates several lipid metabolic pathways. Small molecule inhibitors of lipid biosynthetic pathway enzymes acetyl-CoA carboxylase (ACC), fatty acid synthase, and subtilisin kexin isozyme-1/site-1 protease in HBV-infected HepG2-NTCP cells demonstrated potent and selective reduction of extracellular HBsAg. However, a liver-targeted ACC inhibitor did not show antiviral activity in HBV-infected liver chimeric mice, despite evidence of on-target engagement. Our study suggests that while HBsAg production may be dependent on hepatic de novo lipogenesis in vitro, this may be overcome by extrahepatic sources (such as lipolysis or diet) in vivo. Thus, a combination of agents targeting more than one lipid metabolic pathway may be necessary to reduce HBsAg levels in patients with chronic HBV infection. [ABSTRACT FROM AUTHOR]

Lipid ratios and the triglyceride and glucose index (TyG) could be a simple biochemical marker of insulin resistance (IR). The current study was carried out to examine the correlation between triglyceride to high-density lipoprotein-cholesterol (TG/HDL-C), total cholesterol to HDL-C (TC/HDL-C), low-density lipoprotein-cholesterol to HDL-C ratio (LDL-C/HDL-C), as well as TyG index with the severity and mortality of severe coronavirus disease 2019 (COVID-19). A total of 1228 confirmed COVID-19 patients were included in the current research. Regression models were performed to evaluate the correlation between the lipid index and severity and mortality of COVID-19. The TyG index and TG/HDL-C levels were significantly higher in the severe patients (P<0.05). TG/HDL-C, LDL-C/HDL-C, TC/HDL-C ratios, and TyG index were significantly lower in survivor cases (P<0.05). Multivariate logistic regression analysis demonstrated that predictors of the severity adjusted for age, sex and BMI were TyG index, TG/HDL-C ratio (OR = 1.42 CI:1.10–1.82, OR = 1.06 CI: 1.02–1.11, respectively). This analysis showed that TG/HDL-C, TC/HDL-C, LDL-C/HDL-C ratios, and TyG index statistically are correlated with COVID-19 mortality (OR = 1.12 CI:1.06–1.18, OR = 1.24 CI:1.05–1.48, OR = 1.47 CI:1.19–1.80, OR = 1.52 CI:1.01–2.31, respectively). In summary, the TyG index and lipid ratios such as TC/HDL-C, TG/HDL-C, LDL-C/HDL-C could be used as an early indicator of COVID-19 mortality. Furthermore, the study revealed that TyG index and TG/HDL-C indices are biochemical markers of COVID-19 severe prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Information on LDL's dynamic behaviour of LDL (i.e. production rate and fractional catabolic rate) are of interest if pathologies, lipid-lowering strategies or LDL-metabolism itself are investigated. Determination of these rates is costly and elaborate. Here we studied the interrelationship of LDL mass, its composition and other lipoproteins. Based on this data, we deducted information about LDL's dynamic behaviour. Methods: Lipoprotein profiles of n = 236 participants are evaluated. Plasma was separated by sequential ultracentrifugation into VLDL, IDL, LDL and HDL. Additionally, LDL and HDL were separated into subfractions. Stepwise multiple linear regressions were used to study LDL's ApoB mass and lipid composition. Relying on these results and on causation, we constructed a mathematical model to estimate LDL's retention time. Results: The ApoB mass in LDL correlated best among all measured parameters (including corresponding lipid compositions but using no LDL-associated parameters) with the cholesterol ester content in IDL. TG/CE ratios in LDL's subfractions were strongly correlated with the corresponding ratios in IDL and HDL. The constructed mathematical model links the TG/CE ratio of LDL and HDL to LDL's ApoB concentration and enables a good estimate of LDL's retention time in plasma. Discussion: Relying on our statistic evaluations, we assume that i) the production of nascent LDL via IDL as well as ii) LDL's prolonged retention are mapped by the TG/CE ratio in LDL subfractions. HDL's TG/CE ratio is associated with the change in LDL's TG/CE ratio during its retention in plasma. Our mathematical model uses this information and enables–by relying on causation- a good estimation of LDL's retention time. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the correlation between tear film lipid layer thickness and transepidermal water loss (TEWL) from the ocular area in patients with short tear break-up time (TBUT)-type dry eye and healthy controls. Methods: This prospective study included 25 eyes of patients with short TBUT-type dry eye disease and 25 eyes of healthy controls. Results: Tear film lipid layer thickness was measured using an interferometer, and TEWL from the ocular area was measured using a Tewameter TM300 with custom-made goggles. The correlation between tear film lipid layer thickness and TEWL was evaluated. Additionally, other parameters such as TBUT, Schirmer I score, ocular surface staining, the presence and type of meibomian gland dysfunction (MGD), ocular surface disease index (OSDI), and visual analog scale (VAS) scores were evaluated. Tear film lipid layer thickness did not show a significant correlation with TEWL from the ocular area measured using a Tewameter TM300. However, tear film lipid layer thickness was significantly correlated with tear break-up time (p = 0.004) and ocular surface staining by NEI (National Eye Institute) scheme (p = 0.03). TEWL showed positive correlation with the Schirmer I score (p = 0.004). Conclusions: The tear film lipid layer affected the stability of the tear film more than the amount of TEWL in patients with short TBUT dry eye and healthy controls. [ABSTRACT FROM AUTHOR]

The preventive effects of regular exercise on obesity-related health problems are carried over to the non-exercise detraining period, even when physical activity decreases with aging. However, it remains unknown whether regular childhood exercises can be carried over to adulthood. Therefore, this study aimed to investigate the effects of long-term childhood exercise and detraining on lipid accumulation in organs to prevent obesity in adulthood. Four-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF) rats were used as obese animals. OLETF rats were allocated into sedentary and exercise groups: exercise from 4- to 12-week-old and detraining from 12- to 20-week-old. At 12-week-old immediately after the exercise period, regular exercise completely inhibited hyperphagia, obesity, enlarged pancreatic islets, lipid accumulation and lobular inflammation in the liver, hypertrophied adipocytes in the white adipose tissue (WAT), and brown adipose tissue (BAT) whitening in OLETF rats. Additionally, exercise attenuated the decrease in the ratio of muscle wet weight to body weight associated with obesity. Decreased food consumption was maintained during the detraining period, which inhibited obesity and diabetes at 20-week-old after the detraining period. Histologically, childhood exercise inhibited the enlargement of pancreatic islets after the detraining period. In addition, inhibition of lipid accumulation was completely maintained in the WAT and BAT after the detraining period. However, the effectiveness was only partially successful in lipid accumulation and inflammation in the liver. The ratio of muscle wet weight to body weight was maintained after detraining. In conclusion, early long-term regular exercise effectively prevents obesity and diabetes in childhood, and its effectiveness can be tracked later in life. The present study suggests the importance of exercise during childhood and adolescence to inhibit hyperphagia-induced lipid accumulation in metabolic-related organs in adulthood despite exercise cessation. [ABSTRACT FROM AUTHOR]

In addition to statin therapy, Ezetimibe, a non-statin lipid-modifying agent, is increasingly used to reduce low-density lipoprotein cholesterol and atherosclerotic cardiovascular disease risk. Literature suggests the clinical effectiveness of Ezetimibe plus statin (EPS) therapy; however, primary evidence on its economic effectiveness is inconsistent. Hence, we pooled incremental net benefit to synthesise the cost-effectiveness of EPS therapy. We identified economic evaluation studies reporting outcomes of EPS therapy compared with other lipid-lowering therapeutic agents or placebo by searching PubMed, Embase, Scopus, and Tufts Cost-Effective Analysis registry. Using random-effects meta-analysis, we pooled Incremental Net Benefit (INB) in the US $ with a 95% confidence interval (CI). We used the modified economic evaluations bias checklist and GRADE quality assessment for quality appraisal. The pooled INB from twenty-one eligible studies showed that EPS therapy was significantly cost-effective compared to other lipid-lowering therapeutic agents or placebo. The pooled INB (95% CI) was $4,274 (621 to 7,927), but there was considerable heterogeneity (I2 = 84.21). On subgroup analysis EPS therapy is significantly cost-effective in high-income countries [$4,356 (621 to 8,092)], for primary prevention [$4,814 (2,523 to 7,106)], and for payers' perspective [$3,255 (571 to 5,939)], and from lifetime horizon [$4,571 (746 to 8,395)]. EPS therapy is cost-effective compared to other lipid-lowering therapeutic agents or placebo in high-income countries and for primary prevention. However, there is a dearth of evidence from lower-middle-income countries and the societal perspective. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), triggers enhanced accumulation of lipids to generate foamy macrophages (FMs). This process has been often attributed to the surge in the expression of lipid influx genes with a concomitant decrease in those involved in lipid efflux. Here, we define an Mtb-orchestrated modulation of the ubiquitination of lipid accumulation markers to enhance lipid accretion during infection. We find that Mtb infection represses the expression of the E3 ubiquitin ligase, ITCH, resulting in the sustenance of key lipid accrual molecules viz. ADRP and CD36, that are otherwise targeted by ITCH for proteasomal degradation. In line, overexpressing ITCH in Mtb-infected cells was found to suppress Mtb-induced lipid accumulation. Molecular analyses including loss-of-function and ChIP assays demonstrated a role for the concerted action of the transcription factor YY1 and the arginine methyl transferase PRMT5 in restricting the expression of Itch gene by conferring repressive symmetrical H4R3me2 marks on its promoter. Consequently, siRNA-mediated depletion of YY1 or PRMT5 rescued ITCH expression, thereby compromising the levels of Mtb-induced ADRP and CD36 and limiting FM formation during infection. Accumulation of lipids within the host has been implicated as a pro-mycobacterial process that aids in pathogen persistence and dormancy. In line, we found that perturbation of PRMT5 enzyme activity resulted in compromised lipid levels and reduced mycobacterial survival in mouse peritoneal macrophages (ex vivo) and in a therapeutic mouse model of TB infection (in vivo). These findings provide new insights into the role of PRMT5 and YY1 in augmenting mycobacterial pathogenesis. Thus, we posit that our observations could help design novel adjunct therapies and combinatorial drug regimen for effective anti-TB strategies. Author summary: Mycobacterium tuberculosis infection leads to the formation of lipid-laden cells (foamy macrophages-FMs) that offer a favorable shelter for its persistence. During infection, we observe a significant reduction in the expression of the E3 ubiquitin ligase, ITCH. This repression allows the sustenance of key lipid accretion molecules (ADRP and CD36), by curbing their proteasomal degradation. Further, we show the repression of ITCH to be dependent on the concerted action of the bifunctional transcription factor, YY1 and the arginine methyl transferase, PRMT5. NOTCH signaling pathway was identified as a master-regulator of YY1 expression. In vitro and in vivo analyses revealed the significance of PRMT5 in regulating FM formation and consequently mycobacterial burden. [ABSTRACT FROM AUTHOR]

Epidemiological and clinical studies have found associations between depression and cardiovascular disease risk factors, and coronary artery disease patients with depression have worse prognosis. The genetic relationship between depression and these cardiovascular phenotypes is not known. We here investigated overlap at the genome-wide level and in individual loci between depression, coronary artery disease and cardiovascular risk factors. We used the bivariate causal mixture model (MiXeR) to quantify genome-wide polygenic overlap and the conditional/conjunctional false discovery rate (pleioFDR) method to identify shared loci, based on genome-wide association study summary statistics on depression (n = 450,619), coronary artery disease (n = 502,713) and nine cardiovascular risk factors (n = 204,402–776,078). Genetic loci were functionally annotated using FUnctional Mapping and Annotation (FUMA). Of 13.9K variants influencing depression, 9.5K (SD 1.0K) were shared with body-mass index. Of 4.4K variants influencing systolic blood pressure, 2K were shared with depression. ConjFDR identified 79 unique loci associated with depression and coronary artery disease or cardiovascular risk factors. Six genomic loci were associated jointly with depression and coronary artery disease, 69 with blood pressure, 49 with lipids, 9 with type 2 diabetes and 8 with c-reactive protein at conjFDR < 0.05. Loci associated with increased risk for depression were also associated with increased risk of coronary artery disease and higher total cholesterol, low-density lipoprotein and c-reactive protein levels, while there was a mixed pattern of effect direction for the other risk factors. Functional analyses of the shared loci implicated metabolism of alpha-linolenic acid pathway for type 2 diabetes. Our results showed polygenic overlap between depression, coronary artery disease and several cardiovascular risk factors and suggest molecular mechanisms underlying the association between depression and increased cardiovascular disease risk. Author summary: Studies have found associations between depression and both cardiovascular disease risk factors and worse cardiovascular disease prognosis. It is unknown if shared genetic factors contribute to these associations. We applied novel statistical tools for polygenic architectures to investigate if there are common genes for depression, coronary artery disease and cardiovascular risk factors (body mass index, blood pressure, lipids, type 2 diabetes and c-reactive protein). We used the statistical methods the bivariate causal mixture model (MiXeR) and the conditional/conjunctional false discovery rate (pleioFDR) to quantify genome-wide overlap and to identify shared genetic variants. We found extensive genetic overlap. Depression shared 68% of genetic variants with body mass index and 14% and with systolic blood pressure. We also identified 79 unique genomic variants associated with depression and coronary artery disease or the risk factors. Variants associated with increased risk for depression also increased the risk of coronary artery disease, some of the lipids and c-reactive protein levels, while there was a mixed pattern of direction for the other risk factors. Further analyses identified shared genetic variants found in metabolism of alpha-linolenic pathway for type 2 diabetes. [ABSTRACT FROM AUTHOR]

Dynamic physical examination data can provide both cross-sectional and time-series characteristics of cardiovascular health. However, most physical examination databases containing health and disease information have not been fully utilized in China. Hence, this study aimed to analyze dynamic physical examination indicators for cardiovascular health to provide evidence for precise prevention and control of cardiovascular diseases in the primary prevention domain among healthy population with different demographic characteristics in Shanghai. Three-year continuous data were collected from the physical examination center of a hospital in Shanghai from 2018 to 2020, which included a total of 14,044 participants with an average age of 46.51±15.57 years. The cardiovascular status of overall healthy individuals may have a decreasing trend, which is manifested as a significant year-on-year decrease in high-density lipoprotein cholesterol; a significant year-on-year increase in total cholesterol, low-density lipoprotein cholesterol, and blood glucose levels; and a possible increasing trend of diastolic blood pressure, body mass index, and triglycerides. Healthy population with different sex and age groups have various sensitives to cardiovascular physical examination indicators. To conduct more accurate cardiovascular health management and health promotion for key populations in primary prevention, focusing on the dynamic trends of blood pressure, blood lipids, blood glucose, and body mass index in men and changes in total cholesterol in women over time is especially important. The age group of 50–69 years is key for better prevention and control of cardiovascular health. [ABSTRACT FROM AUTHOR]

Background: Progressive fibrous thickening of peritoneal membrane (PM) is a major complication of long-term peritoneal dialysis. TGF-β/SMAD pathway activation, inflammation and neoangiogenesis have an important role in PM changes induced by peritoneal dialysis. Here, we investigated the effects of paclitaxel (PTX) carried in lipid core nanoparticles (LDE) on the development of peritoneal fibrosis (PF) in rats. Methods: To induce PF, 21 male Wistar rats (300-350g) were injected with chlorhexidine gluconate for 15 consecutive days and randomly assigned to three groups: 1)PF, n = 5: no treatment; 2)LDE, n = 8: treated with LDE only, 3/3 days during 15 days; 3)LDE-PTX, n = 8: treated with PTX (4mg/kg) associated with LDE, 3/3 days during 15 days. A Control group without PF induction (n = 5) was designed, received saline solution, 3/3 days. Peritoneum function tests were performed, and anterior abdominal wall samples of the PM were collected for analyses of peritoneal thickness, immunohistochemitry, and gene expression. Results: LDE-PTX treatment preserved the membrane function, maintaining the ultrafiltration rate and mass transfer of glucose at normal levels. LDE-PTX also prevented PM thickening induced by chlorhexidine gluconate injections. LDE-PTX treatment reduced the number of myofibroblasts infiltrating PM and inhibited the cell proliferation. Gene expression of fibronectin, FSP-1, VEGF, TGF-β, and SMAD3 were reduced by LDE-PTX. Conclusions: LDE-PTX was effective to prevent development of PF and preserve the PM filtration capacity in this rat model, with clear-cut actions on pro-fibrotic mechanisms. Thus, LDE-PTX can be candidate for future clinical trials as adjuvant to peritoneal dialysis to prevent PF development, since this preparation is devoid of toxicity as shown previously. [ABSTRACT FROM AUTHOR]

Cardiolipin is known to interact with bacterial and mitochondrial proteins and protein complexes. Unlike in Escherichia coli and Saccharomyces cerevisiae, the synthesis of cardiolipin is essential for growth of Trypanosoma brucei parasites in culture. Inhibition of cardiolipin production has been shown to result in major changes in the T. brucei proteome and energy metabolism, with CLDP43, a mitochondrial protein containing a StaR-related lipid transfer (START)-like domain, being depleted in a cardiolipin-dependent way. We now show that in T. brucei procyclic forms lacking CLDP43, cardiolipin metabolism and mitochondrial function are affected. Using quantitative and qualitative lipid analyses, we found that while steady-state levels of cardiolipin were elevated in CLDP43 knock-out parasites compared to parental cells, de novo formation of cardiolipin was down-regulated. In addition, depletion of CLDP43 resulted in partial loss of mitochondrial membrane potential and decreased ATP production via substrate level phosphorylation. Recombinant CLDP43 was found to bind cardiolipin and phosphatidic acid in lipid overlay experiments, suggesting that it may be involved in transport or synthesis of cardiolipin or its precursors in T. brucei. [ABSTRACT FROM AUTHOR]

The degree of maintaining nutrient intake patterns, conformed in the family, for offspring into adulthood is unknown. The aim of this study was to investigate the correlation between nutrient intakes in three younger-middle-older generations of Tehranian adults by sex. Of individuals who participated in 2012–15 phase of the Tehran Lipid and Glucose Study, 1286 families (4685 subjects), who had at least two members of the family with complete data in two or three generations were entered in this cross-sectional study. The energy and nutrient intakes of parents and their young or adult offspring or grandparents-grandson/granddaughter dyads were compared. The differences were estimated using pairwise t-test and partial correlation. Data of parents with their offspring were paired based on living arrangement. There were 857 fathers (mean age: 55.4±11.1) and 1394 mothers (mean age: 50.1±11.4). The mean age of grandfathers and grandmothers were 69.4±7.9 and 63.7±8.5 respectively. The significant correlation in fathers-sons and father-daughter (living with their parents) pairs were observed for 9 and 7 nutrients, respectively. Correlations for most nutrients were significant for mother-daughter or sons (living with their parents) dyads. The mean percentage of energy from total fat and trans-fatty acids of sons or daughters (living with their parents) were higher than their parents. For most nutrients, there were no significant adjusted correlations between parents-adult offspring (living independent of their parents) dyads. Also few nutrient intakes of grandparents-grandson or granddaughter dyads were correlated. The nutrient intakes of adult offspring were not associated with their parents; this correlation for younger and older generations disappeared. There were weak to moderate correlation between nutrient intakes of parent-offspring dyads that lived with their parents. The resemblance was higher for mother-offspring than father-offspring. Overall, total fat and trans-fatty acid intakes of young offspring were higher than their parents. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy but the underlying mechanism remains obscure. The aims of this study are to examine if omental adipose tissue (OMAT) and subcutaneous AT (SCAT) differentially express proinflammatory and lipid metabolic adipokines, and if so, whether their regional differences have implications on lipid metabolism in GDM. Paired samples of OMAT and SCAT were excised from pregnant women in scheduled Cesarean sections with non-obese (NOBS), obese (OBS) and GDM. The results showed that the mRNA of monocyte chemoattractant protein (MCP)-1, macrophage marker CD68, and cytokines IL-6, IL-8, and TNF-α are increased in OMAT from GDM women compared to that in NOBS and OBS women (P<0.05). Glucose and TNF-α dose-dependently enhanced ADM and its receptor components CRLR and RAMPs in human adipocytes. Immunofluorescence showed that ADM and its receptor components are higher in OMAT from GDM women compared to non-GDM women. Further, basal lipolysis was greater in OMAT than in SCAT and ADM stimulates further glycerol release in OMAT, but not in SCAT, and these increases are reduced by ADM antagonist, ADM22-52. We therefore conclude that elevated ADM and its receptor expressions by OMAT, but not by SCAT appear to contribute to the lipid dysregulation in GDM women, and manipulation of ADM may represent one of the novel approaches in minimizing the risk of GDM-related fetal overgrowth. [ABSTRACT FROM AUTHOR]

In this work, the Longissimus thoracis pig skeletal muscle was used as a model to investigate the impact of two different diets, supplemented with n-3 polyunsaturated fatty acids from extruded linseed (L) and polyphenols from grape skin and oregano extracts (L+P), on the lipidomic profile of meat. A standard diet for growing-finishing pigs (CTRL) was used as a control. Changes in lipids profile were investigated through an untargeted lipidomics and transcriptomics combined investigation. The lipidomics identified 1507 compounds, with 195 compounds fitting with the MS/MS spectra of LipidBlast database. When compared with the CTRL group, the L+P diet significantly increased 15 glycerophospholipids and 8 sphingolipids, while the L diet determined a marked up-accumulation of glycerolipids. According to the correlations outlined between discriminant lipids and genes, the L diet may act preventing adipogenesis and the related inflammation processes, while the L+P diet promoted the expression of genes involved in lipids' biosynthesis and adipogenic extracellular matrix formation and functioning. [ABSTRACT FROM AUTHOR]

Apicomplexa are obligate intracellular parasites responsible for major human infectious diseases such as toxoplasmosis and malaria, which pose social and economic burdens around the world. To survive and propagate, these parasites need to acquire a significant number of essential biomolecules from their hosts. Among these biomolecules, lipids are a key metabolite required for parasite membrane biogenesis, signaling events, and energy storage. Parasites can either scavenge lipids from their host or synthesize them de novo in a relict plastid, the apicoplast. During their complex life cycle (sexual/asexual/dormant), Apicomplexa infect a large variety of cells and their metabolic flexibility allows them to adapt to different host environments such as low/high fat content or low/high sugar levels. In this review, we discuss the role of lipids in Apicomplexa parasites and summarize recent findings on the metabolic mechanisms in host nutrient adaptation. [ABSTRACT FROM AUTHOR]

While fatty acid metabolism is altered under physiological conditions, alterations can also be maladaptive in diseases such as diabetes and heart failure. Peroxisome Proliferator Activated Receptor α (PPARα) is a transcription factor that regulates fat metabolism but its role in regulating lipid storage in the heart is unclear. The aim of this study is to improve our understanding of how cardiac PPARα regulates cardiac health and lipid accumulation. To study the role of cardiac PPARα, tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR-/-) were treated for 5 days with tamoxifen and then studied after 1–2 months. Under baseline conditions, cPPAR-/- mice appear healthy with normal body weight and mortality is not altered. Importantly, cardiac hypertrophy or reduced cardiac function was also not observed at baseline. Mice were fasted to elevate circulating fatty acids and induce cardiac lipid accumulation. After fasting, cPPAR-/- mice had dramatically lower cardiac triglyceride levels than control mice. Interestingly, cPPAR-/- hearts also had reduced Plin2, a key protein involved in lipid accumulation and lipid droplet regulation, which may contribute to the reduction in cardiac lipid accumulation. Overall, this suggests that a decline in cardiac PPARα may blunt cardiac lipid accumulation by decreasing Plin2 and that independent of differences in systemic metabolism a decline in cardiac PPARα does not seem to drive pathological changes in the heart. [ABSTRACT FROM AUTHOR]

On their way to the oocyte, sperm cells are subjected to oxidative stress, which may trigger the oxidation of phospholipids (PL). Applying MALDI-TOF MS, HPTLC and ESI-IT MS, we comparatively analyzed the PL compositions of semen and blood of species differing in their reproductive systems and types of nutrition (bull, boar, stallion, lion and man) with regard to the sensitivity to oxidation as well as the accumulation of harmful lyso-PL (LPL), transient products of lipid oxidation. In addition, the protective capacity of seminal fluid (SF) was also examined. The PL composition of erythrocytes and blood plasma is similar across the species, while pronounced differences exist for sperm and SF. Since the blood function is largely conserved across mammalian species, but the reproductive systems may vary in many aspects, the obtained results suggest that the PL composition is not determined by the type of nutrition, but by the relatedness of species and by functional requirements of cell membranes such as fluidity. Sperm motion and fertilization of oocytes require a rather flexible membrane, which is accomplished by significant moieties of unsaturated fatty acyl residues in sperm lipids of most species, but implies a higher risk of oxidation. Due to a high content of plasmalogens (alkenyl ether lipids), bull sperm are most susceptible to oxidation. Our data indicate that bull sperm possess the most effective protective power in SF. Obviously, a co-evolution of PL composition and protective mechanisms has occurred in semen and is related to the reproductive characteristics. Although the protective capacity in human SF seems well developed, we recorded the most pronounced individual contaminations with LPL in human semen. Probably, massive oxidative challenges related to lifestyle factors interfere with natural conditions. [ABSTRACT FROM AUTHOR]

Membrane proteins require protein machineries to insert their hydrophobic transmembrane domains (TMDs) into the lipid bilayer. A functional analysis of protein insertases in this issue of PLOS Biology reveals that the fundamental mechanism of membrane protein insertion is universally conserved. Membrane proteins require protein machineries to insert their hydrophobic transmembrane domains into the lipid bilayer. This Primer explores the implications of a new PLOS Biology study of protein insertases which reveals that the fundamental mechanism of membrane protein insertion is universally conserved. [ABSTRACT FROM AUTHOR]

Large-scale molecular profiling and genotyping provide a unique opportunity to systematically compare the genetically predicted effects of therapeutic targets on the human metabolome. We firstly constructed genetic risk scores for 8 drug targets on the basis that they primarily modify low-density lipoprotein (LDL) cholesterol (HMGCR, PCKS9, and NPC1L1), high-density lipoprotein (HDL) cholesterol (CETP), or triglycerides (APOC3, ANGPTL3, ANGPTL4, and LPL). Conducting mendelian randomisation (MR) provided strong evidence of an effect of drug-based genetic scores on coronary artery disease (CAD) risk with the exception of ANGPTL3. We then systematically estimated the effects of each score on 249 metabolic traits derived using blood samples from an unprecedented sample size of up to 115,082 UK Biobank participants. Genetically predicted effects were generally consistent among drug targets, which were intended to modify the same lipoprotein lipid trait. For example, the linear fit for the MR estimates on all 249 metabolic traits for genetically predicted inhibition of LDL cholesterol lowering targets HMGCR and PCSK9 was r2 = 0.91. In contrast, comparisons between drug classes that were designed to modify discrete lipoprotein traits typically had very different effects on metabolic signatures (for instance, HMGCR versus each of the 4 triglyceride targets all had r2 < 0.02). Furthermore, we highlight this discrepancy for specific metabolic traits, for example, finding that LDL cholesterol lowering therapies typically had a weak effect on glycoprotein acetyls, a marker of inflammation, whereas triglyceride modifying therapies assessed provided evidence of a strong effect on lowering levels of this inflammatory biomarker. Our findings indicate that genetically predicted perturbations of these drug targets on the blood metabolome can drastically differ, despite largely consistent effects on risk of CAD, with potential implications for biomarkers in clinical development and measuring treatment response. [ABSTRACT FROM AUTHOR]

Aims: To explore differences in the use of lipid lowering therapy and/or achievement of lipid guideline targets in patients with and without prior depression and influence of sex in very high-risk coronary patients. Methods & findings: A retrospective observational cohort study was conducted using individual-level linked electronic health record data in patients who underwent percutaneous coronary intervention (2012–2017) in Wales. The cohort comprised of 13,781 patients (27.4% female), with 26.1% having prior depression. Lipid levels were recorded in 10,050 patients of whom 25% had depression. History of depression was independently associated with not having lipids checked (OR 0.79 95%CI 0.72–0.87 p<0.001). Patients with prior depression were less likely to achieve targets for low density lipoprotein cholesterol (LDL-C <1.8mmol/l), non-high density lipoprotein cholesterol (non-HDL-C <2.6mmol/l) and triglycerides (<2.3mmol/l) than patients without depression (OR 0.86 95%CI 0.78–0.96 p = 0.007, OR 0.80 95%CI 0.69–0.92 p = 0.003 & OR 0.69 95CI% 0.61–0.79 p<0.001 respectively). Females were less likely to achieve targets for LDL-C and non-HDL-C than males (OR 0.55 95%CI 0.50–0.61 p<0.001 & OR 0.63 95%CI 0.55–0.73 p<0.001). There was an additive effect of depression and sex; females with depression were not only least likely to be tested (OR 0.74 95%CI 0.65–0.84 p<0.001) but also (where levels were known) less likely to achieve LDL-C (OR 0.47 95%CI 0.41–0.55 p<0.001) and non-HDL-C targets (OR 0.50 95%CI 0.41–0.60 p<0.001). It was not possible to look at the influence of medication adherence on achievement of lipid targets due to limitations of the use of anonymised routinely-held clinical care data. Conclusion: Patients with prior depression were less likely to have their lipids monitored and achieve guideline targets within 1-year. Females with depression are the least likely to be tested and achieve lipid targets, suggesting not only a greater risk of future events, but also an opportunity to improve care. [ABSTRACT FROM AUTHOR]

Chlamydia trachomatis causes genital and ocular infections in humans. This bacterial pathogen multiplies exclusively within host cells in a characteristic vacuole (inclusion) and delivers proteins such as inclusion membrane proteins (Incs) into the host cell. Here, we identified CT006 as a novel C. trachomatis protein that when expressed ectopically eukaryotic cells can associate with lipid droplets (LDs). A screen using Saccharomyces cerevisiae identified two Incs causing vacuolar protein sorting defects and seven Incs showing tropism for eukaryotic organelles. Ectopic expression in yeast and mammalian cells of genes encoding different fragments of CT006 revealed tropism for the endoplasmic reticulum and LDs. We identified a LD-targeting region within the first 88 amino acid residues of CT006, and positively charged residues important for this targeting. Comparing with the parental wild-type strain, cells infected by a newly generated C. trachomatis strain overproducing CT006 with a double hemagglutinin tag showed a slight increase in the area occupied by LDs within the inclusion region. However, we could not correlate this effect with the LD-targeting regions within CT006. We further showed that both the amino and carboxy-terminal regions of CT006, flanking the Inc-characteristic bilobed hydrophobic domain, are exposed to the host cell cytosol during C. trachomatis infection, supporting their availability to interact with host cell targets. Altogether, our data suggest that CT006 might participate in the interaction of LDs with C. trachomatis inclusions. [ABSTRACT FROM AUTHOR]

Spider venom GDPD-like phospholipases D (SicTox) have been identified to be one of the major toxins in recluse spider venom. They are divided into two major clades: the α clade and the β clade. Most α clade toxins present high activity against lipids with choline head groups such as sphingomyelin, while activities in β clade toxins vary and include preference for substrates containing ethanolamine headgroups (Sicarius terrosus, St_βIB1). A structural comparison of available structures of phospholipases D (PLDs) reveals a conserved aromatic cage in the α clade. To test the potential influence of the aromatic cage on membrane-lipid specificity we performed molecular-dynamics (MD) simulations of the binding of several PLDs onto lipid bilayers containing choline headgroups; two SicTox from the α clade, Loxosceles intermedia αIA1 (Li_αIA) and Loxosceles laeta αIII1 (Ll_αIII1), and one from the β clade, St_βIB1. The simulation results reveal that the aromatic cage captures a choline-headgroup and suggest that the cage plays a major role in lipid specificity. We also simulated an engineered St_βIB1, where we introduced the aromatic cage, and this led to binding with choline-containing lipids. Moreover, a multiple sequence alignment revealed the conservation of the aromatic cage among the α clade PLDs. Here, we confirmed that the i-face of α and β clade PLDs is involved in their binding to choline and ethanolamine-containing bilayers, respectively. Furthermore, our results suggest a major role in choline lipid recognition of the aromatic cage of the α clade PLDs. The MD simulation results are supported by in vitro liposome binding assay experiments. Author summary: Envenomation following bites from recluse spiders (Loxosceles) causes loxoscelism, a necrotic tissue breakdown in mammals, and leads to skin degeneration and systemic reactions in the worst case. Recluse spiders belong to the Sicariidae family which also includes six-eyed sand spiders in the genera Sicarius and Hexopthalma. While sicariid spiders are found natively on all continents except Australia, treatments of loxoscelism are typically antibody based and available in some regions of the Americas. Sphingomyelinase D/phospholipase D enzymes are one of the major toxins in venom of sicariid spiders, and have been divided in two clades called α and β. The activity of α and β clades toxins differs; most α clade toxins present high activity against lipids with choline headgroups (-N (CH3)3+) such as sphingomyelin, while activities in β clade toxins vary and include preference for substrates containing ethanolamine headgroups (-NH3+). When comparing the structures of two α clade toxins and one β clade toxin, we noticed the presence in the α clade toxins only of a cage consisting of three aromatic amino acids. In this work we used numerical molecular simulations to probe the role of this cage in the preference of α clade toxins for choline head groups over ethanolamine head groups. [ABSTRACT FROM AUTHOR]

The influence of cholesterol fraction in the membranes of giant unilamellar vesicles (GUVs) on their size distributions and bending moduli has been investigated. The membranes of GUVs were synthesized by a mixture of two elements: electrically neutral lipid 1, 2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and cholesterol and also a mixture of three elements: electrically charged lipid 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DOPG), DOPC and cholesterol. The size distributions of GUVs have been presented by a set of histograms. The classical lognormal distribution is well fitted to the histograms, from where the average size of vesicle is obtained. The increase of cholesterol content in the membranes of GUVs increases the average size of vesicles in the population. Using the framework of Helmholtz free energy of the system, the theory developed by us is extended to explain the experimental results. The theory determines the influence of cholesterol on the bending modulus of membranes from the fitting of the proper histograms. The increase of cholesterol in GUVs increases both the average size of vesicles in population and the bending modulus of membranes. [ABSTRACT FROM AUTHOR]

Background: Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa.Methods and Findings: Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)), and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample summary-level Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB, and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis, but adjustment for HDL, TG, and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per standard deviation (SD) = 1.091; 95% CI 1.028 to 1.157; P = 0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per SD = 1.068; 95% CI 1.005 to 1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per SD = 1.078; 95% CI 0.999 to 1.163; P = 0.055) and early age onset PCa (MVMR ORIVW per SD = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilised to minimise the effect of pleiotropy, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings.Conclusions: We observed that genetically predicted Lp(a) concentrations were associated with an increased PCa risk. Future studies are required to understand the underlying biological pathways of this finding, as it may inform PCa prevention through Lp(a)-lowering strategies. [ABSTRACT FROM AUTHOR]

In this study, 5 sterols were isolated and purified from Laminaria japonica, commonly known as edible brown seaweed, and their structures were identified based on detailed chemical methods and spectroscopic analyses. Spectroscopic analyses characterized 5 sterols as 29-Hydroperoxy-stigmasta-5,24(28)-dien-3β-ol, saringosterol (24-vinyl-cholest-5-ene-3β,24-diol), 24-methylenecholesterol, fucosterol (stigmasta-5,24-diene-3β-ol), and 24-Hydroperoxy-24-vinyl-cholesterol. The bioactivities of these sterols were tested using lipid peroxidation (LPO) and cyclooxygenase (COX-1 and -2) enzyme inhibitory assays. Fucosterol exhibited the highest COX-1 and -2 enzyme inhibitory activities at 59 and 47%, respectively. Saringosterol, 24-methylenecholesterol and fucosterol showed higher LPO inhibitory activity at >50% than the other compounds. In addition, the results of molecular docking revealed that the 5 sterols were located in different pocket of COX-1 and -2 and fucosterol with tetracyclic skeletons and olefin methine achieved the highest binding energy (-7.85 and -9.02 kcal/mol) through hydrophobic interactions and hydrogen bond. Our results confirm the presence of 5 sterols in L. japonica and its significant anti-inflammatory and antioxidant activity. [ABSTRACT FROM AUTHOR]

Coffee beans contain high polyphenol content, which have the potential to modulate the intestinal microbiota, and possibly attenuate weight gain and the associated dyslipidemia. This study investigated the effect of freeze-dried coffee solution (FCS) consumption on physiological parameters, lipid profile, and microbiota of Wistar rats fed a high-fat diet (HF) or control diet (CT). FCS combined with a high-fat diet increased the fecal and cecal Bifidobacterium spp. population and decreased the cecal Escherichia coli population and intestinal Il1b mRNA level. Regardless of the diet type, FCS increased the serum high-density lipoprotein cholesterol (HDL-C); however, it did not affect body weight, food intake, low-density lipoprotein, triglycerides, fecal bile acids, and intestinal Il6 mRNA levels. The high-fat diet increased weight gain, hepatic cholesterol and triglycerides, fecal bile acids, and the fecal and cecal Lactobacillus spp. population, and reduced food intake, the fecal E. coli population, and intestinal Il6 mRNA level. The results suggest that FCS consumption exhibits positive health effects in rats fed a high-fat diet by increasing Bifidobacterium spp. population and HDL-C reverse cholesterol transport, and by reducing Il1b mRNA level. However, FCS administration at a dose of 0.39 g/100 g diet over an eight-week period was not effective in controlling food intake, and consequently, preventing weight gain in rats of high-fat diet-induced obesity model. [ABSTRACT FROM AUTHOR]

For long-term treatment of hepatitis B virus (HBV) infection, switching from tenofovir-disoproxil-fumarate (TDF) to tenofovir-alafenamide (TAF) may prevent renal dysfunction and bone loss. However, the precise effects of this switch on the blood lipid profile remain to be clarified. This is an important issue as TDF is known to have effects on both low- and high-density lipids. Therefore, our retrospective multi-center study aimed to evaluate the effects of switching from TDF to TAF on the lipid profile of patients with HBV infection. Samples were obtained prior to the switch from TDF to TAF and at 6–12 months after TAF initiation. In some cases, additional samples obtained pre- and post-TDF administration were available for analysis. Serum cholesterol levels, including oxidized-low-density lipoprotein (LDL) and non-high-density lipoprotein-cholesterol (HDL-c), and the rate of dyslipidemia, according to the NCEP-ATP III lipid risk classification, were analyzed. The data from 69 patients were analyzed, including 33 patients with pre- and post-TDF-initiation serum samples. Total cholesterol (T-chol), HDL-c, LDL-c, non-HDL-c, and oxidized LDL levels increased significantly after switching to TAF. With regard to sequential changes pre- to post-TAF, TDF was associated with significantly lower serum T-chol, HDL-c, and oxidized LDL-c levels, with T-chol, HDL-c, LDL-c, and oxidized LDL-c levels increasing significantly after the switch. The switch from TDF to TAF was also associated with an increase in the rate of dyslipidemia, from 33% to 39%, with an increase in the rate of severe dyslipidemia of 1.4% and 5.8%, based on T-chol and LDL-c levels. Of note, no cases of severe dyslipidemia were detected pre-TAF treatment. As oxidized LDL-c and non-HDL-c are strongly associated with atherosclerosis development, careful monitoring of lipid is needed after switching from TDF to TAF in this clinical population. [ABSTRACT FROM AUTHOR]

Lipid droplets (LDs) have increasingly been recognized as an essential organelle for eukaryotes. Although the biochemistry of lipid synthesis and degradation is well characterized, the regulation of LD dynamics, including its formation, maintenance, and secretion, is poorly understood. Here, we report that mice lacking Occludin (Ocln) show defective lipid metabolism. We show that LDs were larger than normal along its biogenesis and secretion pathway in Ocln null mammary cells. This defect in LD size control did not result from abnormal lipid synthesis or degradation; rather, it was because of secretion failure during the lactation stage. We found that OCLN was located on the LD membrane and was bound to essential regulators of lipid secretion, including BTN1a1 and XOR, in a C-terminus–dependent manner. Finally, OCLN was a phosphorylation target of Src kinase, whose loss causes lactation failure. Together, we demonstrate that Ocln is a downstream target of Src kinase and promotes LD secretion by binding to BTN1a1 and XOR. Lipid droplets are an essential eukaryotic organelle, but how they are secreted has remained unclear. This study shows that the tight junction protein Occludin is a phosphorylation target of Src kinase; Occludin binds to BTN1A1 and XOR to facilitate lipid droplet secretion in mammary epithelial cells. [ABSTRACT FROM AUTHOR]

Aim: To study the possible effects of a dietary intervention with minimal and unprocessed foods, high in natural saturated fats on the lipid profile and body mass index of children. Method: This study combines three intervention studies; one non-randomized retrospective cohort study and two randomized controlled trials, to a pooled analysis. The intervention group received a dietary intervention of minimal and unprocessed foods for three to six months, consisting of five times per week green vegetables, three times per week beef, daily 200–300 mL whole cow's milk (3.4% fat) and whole dairy butter (80% fat) on each slice of bread. The control group continued their usual dietary habits. Raw data of the three intervention studies where combined into one single dataset for data analysis, using mixed effects analysis of covariance to test the effects of the dietary advice on the main study outcomes, which are measurements of the lipid profile. Results: In total, 267 children aged 1 to 16 years were followed. 135 children were included in the intervention group and 139 children in the control group. Characteristics (age, gender and follow-up period) were equally distributed between the groups at baseline. In the intervention group HDL-cholesterol increased significantly from 1.22 mmol/L, 95% confidence interval (CI) 1.14–1.32 to 1.42 mmol/L 95% CI 1.30–1.65 (p = 0.007). The increase over time in HDL cholesterol in the intervention group was significantly different compared to the increase in the control group (from 1.26 mmol/L, 95% CI 1.19–1.35, to 1.30 mmol/L, 95% CI 1.26–1.37) (p = 0.04). Due to the increased HDL concentration in the intervention group, the total cholesterol/HDL cholesterol ratio decreased significantly from 3.70 mmol/L, 95% CI 3.38–3.87, to 3.25 mmol/L, 95% CI 2.96–3.31 (p = 0.05). Conclusion: Consumption of minimal and unprocessed foods (high in natural saturated fats) has favourable effects on HDL cholesterol in children. Therefore, this dietary advice can safely be recommended to children. [ABSTRACT FROM AUTHOR]

T cell receptors (TCRs) encode the history of antigenic challenge within an individual and have the potential to serve as molecular markers of infection. In addition to peptide antigens bound to highly polymorphic MHC molecules, T cells have also evolved to recognize bacterial lipids when bound to non-polymorphic CD1 molecules. One such subset, germline-encoded, mycolyl lipid-reactive (GEM) T cells, recognizes mycobacterial cell wall lipids and expresses a conserved TCR-ɑ chain that is shared among genetically unrelated individuals. We developed a quantitative PCR assay to determine expression of the GEM TCR-ɑ nucleotide sequence in human tissues and blood. This assay was validated on plasmids and T cell lines. We tested blood samples from South African subjects with or without tuberculin reactivity or with active tuberculosis disease. We were able to detect GEM TCR-ɑ above the limit of detection in 92% of donors but found no difference in GEM TCR-ɑ expression among the three groups after normalizing for total TCR-ɑ expression. In a cohort of leprosy patients from Nepal, we successfully detected GEM TCR-ɑ in 100% of skin biopsies with histologically confirmed tuberculoid and lepromatous leprosy. However, GEM TCR-ɑ expression was not different between leprosy patients and control subjects after normalization. Thus, GEM T cells constitute part of the T cell repertoire in the skin. Further, these results reveal the feasibility of developing a simple, field deployable molecular diagnostic based on mycobacterial lipid antigen-specific TCR sequences that are readily detectable in human tissues and blood independent of genetic background. Author summary: Our T cell receptor repertoires are unique to each individual and encode the history of our antigenic exposures. Because of this property, they can act as markers of infection. Due to the diversity of T cell receptors, analyzing an individual's repertoire requires advanced sequencing and machine learning methods. However, there are also subsets of T cells that express conserved T cell receptors shared among genetically unrelated individuals. One such subset, germline-encoded, mycolyl lipid-reactive (GEM) T cells, recognizes mycobacterial cell wall lipids. To determine if we could measure expression of these T cells with a simple assay, we developed a quantitative real-time PCR assay that was validated on plasmids and T cell lines. We then determined whether we could detect the GEM T cell receptor sequence in individuals with or without exposure to Mycobacterium tuberculosis or Mycobacterium leprae. We found that we could detect the GEM T cell receptor in the blood or skin of most individuals, though expression levels did not distinguish between uninfected or infected states. These data show that simple assays to measure mycobacteria-specific T cell receptor sequences are feasible and further advancements focusing on more disease-specific T cell receptors may allow for development of field-friendly diagnostics. [ABSTRACT FROM AUTHOR]

This study investigated 12-year blood lipid trajectories and whether these trajectories are modified by smoking and lipid lowering treatment in older Russians. To do so, we analysed data on 9,218 Russian West-Siberian Caucasians aged 45–69 years at baseline participating in the international HAPIEE cohort study. Mixed-effect multilevel models were used to estimate individual level lipid trajectories across the baseline and two follow-up examinations (16,445 separate measurements over 12 years). In all age groups, we observed a reduction in serum total cholesterol (TC), LDL-C and non-HDL-C over time even after adjusting for sex, statin treatment, hypertension, diabetes, social factors and mortality (P<0.01). In contrast, serum triglyceride (TG) values increased over time in younger age groups, reached a plateau and decreased in older age groups (> 60 years at baseline). In smokers, TC, LDL-C, non-HDL-C and TG decreased less markedly than in non-smokers, while HDL-C decreased more rapidly while the LDL-C/HDL-C ratio increased. In subjects treated with lipid-lowering drugs, TC, LDL-C and non-HDL-C decreased more markedly and HDL-C less markedly than in untreated subjects while TG and LDL-C/HDL-C remained stable or increased in treatment naïve subjects. We conclude, that in this ageing population we observed marked changes in blood lipids over a 12 year follow up, with decreasing trajectories of TC, LDL-C and non-HDL-C and mixed trajectories of TG. The findings suggest that monitoring of age-related trajectories in blood lipids may improve prediction of CVD risk beyond single measurements. [ABSTRACT FROM AUTHOR]

Physical activity (PA) levels are low in Gulf Cooperation Council countries (GCC; Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, United Arab Emirates). We carried out a systematic review (PROSPERO registration number 131817) to assess the effect of interventions to increase PA levels in this region. We also assessed their effects on anthropometry and cardiovascular risk. A systematic search of six databases (Medline, EMBASE, SPORTDiscus, CINAHL, Cochrane, Web of Science) was performed to identify randomized and non-randomized intervention studies performed in adults and children published between January 1985 and November 2020. We included studies published in English or Arabic, and included PA interventions regardless of setting, delivery, and duration. The primary outcomes were changes in PA duration and intensity. Secondary outcomes included anthropometric measures (e.g., weight, body mass index) and cardiovascular risk profiles (e.g., lipid measures, blood glucose). Two independent reviewers screened studies in accordance with pre-determined criteria, extracted data, assessed risk of bias (Cochrane Risk of Bias 2 and Newcastle Ottawa Scale) and undertook a narrative synthesis. From 13,026 records identified, 14 studies were included. Nine studies focussed exclusively on changing PA behaviour, resulting in statistically significant increases in step count ranging from an additional 757 steps/day (95% confidence interval [CI] 0–1,513) to 3,853 steps/day (95% CI 3,703–4,002). Five identified studies were multi-component lifestyle interventions, targeting people at higher risk (due to obesity or type 2 diabetes). Evidence for increases in PA from multi-component studies was limited, although improvements were seen in outcomes e.g. body weight and blood lipid levels. In conclusion, relatively few studies have focussed on changing PA behaviour, despite the urgent need in the GCC. Limited evidence suggested that pedometer-based programmes encouraging step counting and walking were effective in promoting PA, at least in the short term. Policies to roll out such interventions should be implemented and evaluated. [ABSTRACT FROM AUTHOR]

Coronary heart disease (CHD) is a prevalent complication of type 2 diabetes mellitus (T2DM). The atherogenic low-density lipoprotein (LDL) cholesterol is an established risk factor of cardiovascular disease, and evidence also suggests that postprandial plasma glucose (PPG) levels closely delineate CHD mortality in diabetes. The investigators hypothesized that postprandial plasma glucose excursion (PPGE), defined as the difference between 2-hour PPG and fasting plasma glucose (FPG), may be associated with plasma LDL cholesterol levels in patients with T2DM. This study enrolled diabetic participants for whom FPG and lipid profile were sampled after a 12-hour fast, followed by PPG sampling two hours after consuming a standard meal with 75 grams of carbohydrates. The study enrolled 379 participants who were divided into PPGE tertiles according to the difference between their 2-hour PPG and FPG. Participants in the highest PPGE tertile had considerably greater plasma LDL cholesterol levels than patients in the lowest tertile (126.7 mg/dL vs. 99.5 mg/dL, P <0.001). Linear regression analysis also demonstrated that the PPGE was positively correlated with plasma LDL cholesterol levels (β coefficient: 0.165, P < 0.001). Postprandial glucose excursion positively correlated with plasma LDL cholesterol levels in individuals with T2DM. Participants with raised PPGE harbored greater LDL cholesterol levels than those with lower postprandial glucose fluctuations. Therefore, postprandial glucose excursion is associated with an atherogenic lipid profile and may be a modifiable risk factor of diabetic CHD. [ABSTRACT FROM AUTHOR]

In this Perspective, Dimitrios Sagris, Stephanie Harrison, and Gregory Lip discuss new evidence concerning the paradoxical relationship between circulating lipids and atrial fibrillation. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infection induces the degradation and decreases the secretion of apolipoprotein B (ApoB). Impaired production and secretion of ApoB-containing lipoprotein is associated with an increase in hepatic steatosis. Therefore, HCV infection-induced degradation of ApoB may contribute to hepatic steatosis and decreased lipoprotein secretion, but the mechanism of HCV infection-induced ApoB degradation has not been completely elucidated. In this study, we found that the ApoB level in HCV-infected cells was regulated by proteasome-associated degradation but not autophagic degradation. ApoB was degraded by the 20S proteasome in a ubiquitin-independent manner. HCV induced the oxidation of ApoB via oxidative stress, and oxidized ApoB was recognized by the PSMA5 and PSMA6 subunits of the 20S proteasome for degradation. Further study showed that ApoB was degraded at endoplasmic reticulum (ER)-associated lipid droplets (LDs) and that the retrotranslocation and degradation of ApoB required Derlin-1 but not gp78 or p97. Moreover, we found that knockdown of ApoB before infection increased the cellular lipid content and enhanced HCV assembly. Overexpression of ApoB-50 inhibited lipid accumulation and repressed viral assembly in HCV-infected cells. Our study reveals a novel mechanism of ApoB degradation and lipid accumulation during HCV infection and might suggest new therapeutic strategies for hepatic steatosis. Author summary: Hepatitis C virus (HCV) infection induces the degradation of apolipoprotein B (ApoB), which is the primary apolipoprotein in low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Impaired production and secretion of ApoB-containing lipoprotein is associated with an increase in hepatic steatosis. Thus, ApoB degradation might contribute to HCV infection-induced fatty liver. Here, we found that ApoB was not degraded through endoplasmic reticulum-associated degradation (ERAD) or autophagy, as reported previously. Instead, HCV infection induced ApoB oxidation through oxidative stress, and oxidatively damaged ApoB could be recognized and directly degraded by the 20S proteasome. We also found that ApoB was retrotranslocated from the endoplasmic reticulum (ER) to lipid droplets (LDs) for degradation. Through overexpression of ApoB-50, which can mediate the assembly and secretion of LDL and VLDL, we confirmed that ApoB degradation contributed to hepatocellular lipid accumulation induced by HCV infection. Additionally, expression of ApoB-50 impaired HCV production due to the observed decrease in lipid accumulation. In this study, we identified new mechanisms of ApoB degradation and HCV-induced lipid accumulation, and our findings might facilitate the development of novel therapeutic strategies for HCV infection-induced fatty liver. [ABSTRACT FROM AUTHOR]

Arenavirus entry into host cells occurs through a low pH-dependent fusion with late endosomes that is mediated by the viral glycoprotein complex (GPC). The mechanisms of GPC-mediated membrane fusion and of virus targeting to late endosomes are not well understood. To gain insights into arenavirus fusion, we examined cell-cell fusion induced by the Old World Lassa virus (LASV) GPC complex. LASV GPC-mediated cell fusion is more efficient and occurs at higher pH with target cells expressing human LAMP1 compared to cells lacking this cognate receptor. However, human LAMP1 is not absolutely required for cell-cell fusion or LASV entry. We found that GPC-induced fusion progresses through the same lipid intermediates as fusion mediated by other viral glycoproteins–a lipid curvature-sensitive intermediate upstream of hemifusion and a hemifusion intermediate downstream of acid-dependent steps that can be arrested in the cold. Importantly, GPC-mediated fusion and LASV pseudovirus entry are specifically augmented by an anionic lipid, bis(monoacylglycero)phosphate (BMP), which is highly enriched in late endosomes. This lipid also specifically promotes cell fusion mediated by Junin virus GPC, an unrelated New World arenavirus. We show that BMP promotes late steps of LASV fusion downstream of hemifusion–the formation and enlargement of fusion pores. The BMP-dependence of post-hemifusion stages of arenavirus fusion suggests that these viruses evolved to use this lipid as a cofactor to selectively fuse with late endosomes. Author summary: Pathogenic arenaviruses pose a serious health threat. The viral envelope glycoprotein GPC mediates attachment to host cells and drives virus entry via endocytosis and low pH-dependent fusion within late endosomes. Understanding the host factors and processes that are essential for arenavirus fusion may identify novel therapeutic targets. To delineate the mechanism of arenavirus entry, we examined cell-cell fusion induced by the Old World Lassa virus GPC proteins at low pH. Lassa GPC-mediated fusion was augmented by the human LAMP1 receptor and progressed through lipid curvature-sensitive intermediates, such as hemifusion (merger of contacting leaflets of viral and cell membrane without the formation of a fusion pore). We found that most GPC-mediated fusion events were off-path hemifusion structures and that the transition from hemifusion to full fusion and fusion pore enlargement were specifically promoted by an anionic lipid, bis(monoacylglycero)phosphate, which is highly enriched in late endosomes. This lipid also specifically promotes fusion of unrelated New World Junin arenavirus. Our results imply that arenaviruses evolved to use bis(monoacylglycero)phosphate to enter cells from late endosomes. [ABSTRACT FROM AUTHOR]

Coronavirus disease (COVID)-19, as a result of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, has been the direct cause of over 2.2 million deaths worldwide. A timely coordinated host-immune response represents the leading driver for restraining SARS-CoV-2 infection. Indeed, several studies have described dysregulated immunity as the crucial determinant for critical illness and the failure of viral control. Improved understanding and management of COVID-19 could greatly reduce the mortality and morbidity caused by SARS-CoV-2. One aspect of the immune response that has to date been understudied is whether lipid mediator production is dysregulated in critically ill patients. In the present study, plasma from COVID-19 patients with either severe disease and those that were critically ill was collected and lipid mediator profiles were determined using liquid chromatography tandem mass spectrometry. Results from these studies indicated that plasma concentrations of both pro-inflammatory and pro-resolving lipid mediator were reduced in critically ill patients when compared with those with severe disease. Furthermore, plasma concentrations of a select group of mediators that included the specialized pro-resolving mediators (SPM) Resolvin (Rv) D1 and RvE4 were diagnostic of disease severity. Interestingly, peripheral blood SPM concentrations were also linked with outcome in critically ill patients, where we observed reduced overall concentrations of these mediators in those patients that did not survive. Together the present findings establish a link between plasma lipid mediators and disease severity in patients with COVID-19 and indicate that plasma SPM concentrations may be linked with survival in these patients. [ABSTRACT FROM AUTHOR]

The mycobacterial membrane protein large 3 (MmpL3) transporter is essential and required for shuttling the lipid trehalose monomycolate (TMM), a precursor of mycolic acid (MA)-containing trehalose dimycolate (TDM) and mycolyl arabinogalactan peptidoglycan (mAGP), in Mycobacterium species, including Mycobacterium tuberculosis and Mycobacterium smegmatis. However, the mechanism that MmpL3 uses to facilitate the transport of fatty acids and lipidic elements to the mycobacterial cell wall remains elusive. Here, we report 7 structures of the M. smegmatis MmpL3 transporter in its unbound state and in complex with trehalose 6-decanoate (T6D) or TMM using single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography. Combined with calculated results from molecular dynamics (MD) and target MD simulations, we reveal a lipid transport mechanism that involves a coupled movement of the periplasmic domain and transmembrane helices of the MmpL3 transporter that facilitates the shuttling of lipids to the mycobacterial cell wall. Mycobacterial membrane protein Large 3 (MmpL3) is a transporter required for shuttling trehalose monomycolate. Structures of M. smegmatis MmpL3 with and without substrate reveal the mechanism by which MmpL3 transports this essential precursor of lipids for the mycobacterial cell wall. [ABSTRACT FROM AUTHOR]

In eukaryotic cells, a subset of cell surface proteins is attached by the glycolipid glycosylphosphatidylinositol (GPI) to the external leaflet of the plasma membrane where they play important roles as enzymes, receptors, or adhesion molecules. Here we present a protocol for purification and mass spectrometry analysis of the lipid moiety of individual GPI-anchored proteins (GPI-APs) in yeast. The method involves the expression of a specific GPI-AP tagged with GFP, solubilization, immunoprecipitation, separation by electrophoresis, blotting onto PVDF, release and extraction of the GPI-lipid moiety and analysis by mass spectrometry. By using this protocol, we could determine the precise GPI-lipid structure of the GPI-AP Gas1-GFP in a modified yeast strain. This protocol can be used to identify the lipid composition of the GPI anchor of distinct GPI-APs from yeast to mammals and can be adapted to determine other types of protein lipidation. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a common gynecological disease that is often accompanied by some metabolic abnormality such as insulin resistance and dyslipidemia. As a non-pharmacological therapy, acupuncture is widely used for the treatment of PCOS, but the effectiveness for insulin resistance and lipid metabolic disorder remains controversial. Objectives: To assess the effectiveness and safety of acupuncture for insulin resistance and lipid metabolic disorder of women with PCOS. Search methods: Eight databases will be searched from inception to June 2021, three clinical trial registration platforms will be searched for relevant trials. Selection criteria: Randomized controlled trials (RCTs) of acupuncture therapy for insulin resistance and lipid metabolic of PCOS will be included. Data collection and analysis: Study screening, data collection, and analysis will be performed by two or more reviewers independently. We will calculate mean difference (MD), standard mean difference (SMD) with 95% confidence intervals (CIs). Data synthesis will be performed with RevMan V.5.3 software and with Stata V.15.0 software when necessary. PROSPERO registration number: CRD42020177846 [ABSTRACT FROM AUTHOR]

Cardiovascular diseases are a major cause of death globally. Epidemiological evidence has linked elevated levels of blood cholesterol with the risk of coronary heart disease. However, lipid-lowering agents, despite their importance for primary prevention, are significantly underused in the United States. The objective of this study was to explore associations among socioeconomic factors and the use of antihyperlipidemic agents in 2018 in U.S. patients with hyperlipidemia by applying a theoretical framework. Data from the 2018 Medical Expenditure Panel Survey were used to identify the population of non-institutionalized U.S. civilians diagnosed with hyperlipidemia. This cross sectional study applied the Andersen Behavioral Model to identify patients' predisposing, enabling, and need factors. Approximately 43 million non-institutionalized adults were diagnosed with hyperlipidemia. With the exception of gender and race, predisposing factors indicated significant differences between patients who used antihyperlipidemic agents and those who did not. The relation between income level and use of antihyperlipidemic agents was significant: X2 (4, N = 3,781) = 7.09, p <.001. Hispanic patients were found to be less likely to receive treatment (OR: 0.62; 95% CI: 0.43–0.88), as observed using a logistic model, with controls for predisposing, enabling, and need factors. Patients without health insurance were less likely to use lipid-lowering agents (OR: 0.33; 95% CI: 0.14–0.77). The present study offers essential data for prioritizing interventions by health policy makers by identifying barriers in utilizing hyperlipidemia therapy. Non-adherence to treatment may lead to severe consequences and increase the frequency of fatal cardiac events in the near future. [ABSTRACT FROM AUTHOR]

A new purification technique is developed for obtaining distribution of giant unilamellar vesicles (GUVs) within a specific range of sizes using dual filtration. The GUVs were prepared using well known natural swelling method. For filtration, different combinations of polycarbonate membranes were implemented in filter holders. In our experiment, the combinations of membranes were selected with corresponding pore sizes–(i) 12 and 10 μm, (ii) 12 and 8 μm, and (iii) 10 and 8 μm. By these filtration arrangements, obtained GUVs size distribution were in the ranges of 6−26 μm, 5–38 μm and 5–30 μm, respectively. In comparison, the size distribution range was much higher for single filtration technique, for example, 6−59 μm GUVs found for a membrane with 12 μm pores. Using this technique, the water-soluble fluorescent probe, calcein, can be removed from the suspension of GUVs successfully. The size distributions were analyzed with lognormal distribution. The skewness became smaller (narrow size distribution) when a dual filtration was used instead of single filtration. The mode of the size distribution obtained in dual filtration was also smaller to that of single filtration. By continuing this process of purification for a second time, the GUVs size distribution became even narrower. After using an extra filtration with dual filtration, two different size distributions of GUVs were obtained at a time. This experimental observation suggests that different size specific distributions of GUVs can be obtained easily, even if GUVs are prepared by different other methods. [ABSTRACT FROM AUTHOR]

The T cell receptor (TCR-CD3) initiates T cell activation by binding to peptides of Major Histocompatibility Complexes (pMHC). The TCR-CD3 topology is well understood but the arrangement and dynamics of its cytoplasmic tails remains unknown, limiting our grasp of the signalling mechanism. Here, we use molecular dynamics simulations and modelling to investigate the entire TCR-CD3 embedded in a model membrane. Our study demonstrates conformational changes in the extracellular and transmembrane domains, and the arrangement of the TCR-CD3 cytoplasmic tails. The cytoplasmic tails formed highly interlaced structures while some tyrosines within the immunoreceptor tyrosine-based activation motifs (ITAMs) penetrated the hydrophobic core of the membrane. Interactions between the cytoplasmic tails and phosphatidylinositol phosphate lipids in the inner membrane leaflet led to the formation of a distinct anionic lipid fingerprint around the TCR-CD3. These results increase our understanding of the TCR-CD3 dynamics and the importance of membrane lipids in regulating T cell activation. Author summary: The T cell receptor (TCR-CD3) detects antigenic peptides displayed by major histocompatibility complexes (pMHC) to instigate activation of T cell-mediated adaptive immunity. Despite significant structural and functional knowledge of the TCR-CD3 topology, the membrane interactions and dynamics of its cytoplasmic moieties remain elusive. Interactions of TCR-CD3 cytoplasmic tails with membrane lipids may regulate their phosphorylation by Src-family kinases, the first intracellular event required for T cell activation. Using the static 3D structure of TCR-CD3 resolved by cryo-electron microscopy, we provide novel insights into the protein-lipid interactions of the complete TCR-CD3 embedded in a bilayer closely mimicking its native membrane environment. Our study sheds light on the dynamics of the TCR-CD3 at near-atomic resolution and further aids in deciphering its activation mechanism. [ABSTRACT FROM AUTHOR]

Fat stored in the form of lipid droplets has long been considered a defining characteristic of cytoplasm. However, recent studies have shown that nuclear lipid droplets occur in multiple cells and tissues, including in human patients with fatty liver disease. The function(s) of stored fat in the nucleus has not been determined, and it is possible that nuclear fat is beneficial in some situations. Conversely, nuclear lipid droplets might instead be deleterious by disrupting nuclear organization or triggering aggregation of hydrophobic proteins. We show here that nuclear lipid droplets occur normally in C. elegans intestinal cells and germ cells, but appear to be associated with damage only in the intestine. Lipid droplets in intestinal nuclei can be associated with novel bundles of microfilaments (nuclear actin) and membrane tubules that might have roles in damage repair. To increase the normal, low frequency of nuclear lipid droplets in wild-type animals, we used a forward genetic screen to isolate mutants with abnormally large or abundant nuclear lipid droplets. Genetic analysis and cloning of three such mutants showed that the genes encode the lipid regulator SEIP-1/seipin, the inner nuclear membrane protein NEMP-1/Nemp1/TMEM194A, and a component of COPI vesicles called COPA-1/α-COP. We present several lines of evidence that the nuclear lipid droplet phenotype of copa-1 mutants results from a defect in retrieving mislocalized membrane proteins that normally reside in the endoplasmic reticulum. The seip-1 mutant causes most germ cells to have nuclear lipid droplets, the largest of which occupy more than a third of the nuclear volume. Nevertheless, the nuclear lipid droplets do not trigger apoptosis, and the germ cells differentiate into gametes that produce viable, healthy progeny. Thus, our results suggest that nuclear lipid droplets are detrimental to intestinal nuclei, but have no obvious deleterious effect on germ nuclei. Author summary: Several human disorders such as obesity are associated with abnormal fat storage. Cells normally store fat in cytoplasmic organelles called lipid droplets. However, recent studies have shown that fat can also form inside of the cell nucleus, and the effects of nuclear fat are not known. Here we use the cell biology and genetics of the model organism C. elegans to study the causes and consequences of nuclear fat. We show that intestinal cells can contain nuclear fat, particularly during high-low-high changes in cytoplasmic fat that involve de novo fat synthesis. Nuclear fat is associated with multiple changes in intestinal nuclei that appear to represent damage and repair. Germ nuclei that normally differentiate into oocytes can also contain nuclear fat. In germ cells, however, even high levels of nuclear fat appear to cause little or no damage. Our results suggest that intestinal nuclei and germ cell nuclei might have different responses to nuclear fat in part because they differ in chromosomal organization at the nuclear envelope. [ABSTRACT FROM AUTHOR]

Irreversible electroporation (IRE) is a nonthermal tumor/cell ablation technique in which a series of high-voltage short pulses are used. As a new approach, we aimed to investigate the rupture of giant unilamellar vesicles (GUVs) using the IRE technique under different osmotic pressures (Π), and estimated the membrane tension due to Π. Two categories of GUVs were used in this study. One was prepared with a mixture of dioleoylphosphatidylglycerol (DOPG), dioleoylphosphatidylcholine (DOPC) and cholesterol (chol) for obtaining more biological relevance while other with a mixture of DOPG and DOPC, with specific molar ratios. We determined the rate constant (kp) of rupture of DOPG/DOPC/chol (46/39/15)-GUVs and DOPG/DOPC (40/60)-GUVs induced by constant electric tension (σc) under different Π. The σc dependent kp values were fitted with a theoretical equation, and the corresponding membrane tension (σoseq) at swelling equilibrium under Π was estimated. The estimated membrane tension agreed well with the theoretical calculation within the experimental error. Interestingly, the values of σoseq were almost same for both types of synthesized GUVs under same osmotic pressure. We also examined the sucrose leakage, due to large osmotic pressure-induced pore formation, from the inside of DOPG/DOPC/chol(46/39/15)-GUVs. The estimated membrane tension due to large Π at which sucrose leaked out was very similar to the electric tension at which GUVs were ruptured without Π. We explained the σc and Π induced pore formation in the lipid membranes of GUVs. [ABSTRACT FROM AUTHOR]

Resolvin D1, a specialized pro-resolving lipid mediator produced from docosahexaenoic acid by 15- and 5-lipoxygenase, exerts anti-inflammatory effects driving to the resolution of inflammation. The present study aimed to elucidate its role in small intestinal damage induced by nonsteroidal anti-inflammatory drug (NSAID). Indomethacin was administered orally to C57BL/6J male mice, which were sacrificed 24 h later to collect small intestine specimens. Before administration of indomethacin, mice were subjected to intraperitoneal treatment with resolvin D1 or oral administration of baicalein, a 15-lipoxygenase inhibitor. Small intestinal damage induced by indomethacin was attenuated by pretreatment with resolvin D1. Furthermore, resolvin D1 reduced the gene expression levels of interleukin-1β, tumor necrosis factor-α, and CXCL1/keratinocyte chemoattractant. Conversely, the inhibition of 15-lipoxygenase activity by baicalein increased the expression of genes coding for these inflammatory cytokines and chemokine, leading to exacerbated small intestinal damage, and reduced the concentration of resolvin D1 in the small intestinal tissue. Exogenous treatment with resolvin D1 negated the deleterious effect of baicalein. 15-lipoxygenase was mainly expressed in the epithelium and inflammatory cells of the small intestine, and its gene and protein expression was not affected by the administration of indomethacin. Inhibition of the resolvin D1 receptor, lipoxin A4 receptor /formyl peptide receptor 2, by its specific inhibitors Boc-1 and WRW4 aggravated indomethacin-induced small intestinal damage. Collectively, these results indicate that resolvin D1 produced by 15-lipoxygenase contributes to mucoprotection against NSAID-induced small intestinal damage through its anti-inflammatory effect. [ABSTRACT FROM AUTHOR]

We report the application of supervised machine learning to the automated classification of lipid droplets in label-free, quantitative-phase images. By comparing various machine learning methods commonly used in biomedical imaging and remote sensing, we found convolutional neural networks to outperform others, both quantitatively and qualitatively. We describe our imaging approach, all implemented machine learning methods, and their performance with respect to computational efficiency, required training resources, and relative method performance measured across multiple metrics. Overall, our results indicate that quantitative-phase imaging coupled to machine learning enables accurate lipid droplet classification in single living cells. As such, the present paradigm presents an excellent alternative of the more common fluorescent and Raman imaging modalities by enabling label-free, ultra-low phototoxicity, and deeper insight into the thermodynamics of metabolism of single cells. [ABSTRACT FROM AUTHOR]

Fish oil supplementation is widely used for reducing serum triglycerides (TAGs) but has mixed effects on other circulating cardiovascular biomarkers. Many genetic polymorphisms have been associated with blood lipids, including high- and low-density-lipoprotein cholesterol (HDL-C, LDL-C), total cholesterol, and TAGs. Here, the gene-diet interaction effects of fish oil supplementation on these lipids were analyzed in a discovery cohort of up to 73,962 UK Biobank participants, using a 1-degree-of-freedom (1df) test for interaction effects and a 2-degrees-of-freedom (2df) test to jointly analyze interaction and main effects. Associations with P < 1×10−6 in either test (26,157; 18,300 unique variants) were advanced to replication in up to 7,284 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Replicated associations reaching 1df P < 0.05 (2,175; 1,763 unique variants) were used in meta-analyses. We found 13 replicated and 159 non-replicated (UK Biobank only) loci with significant 2df joint tests that were predominantly driven by main effects and have been previously reported. Four novel interaction loci were identified with 1df P < 5×10−8 in meta-analysis. The lead variant in the GJB6-GJB2-GJA3 gene cluster, rs112803755 (A>G; minor allele frequency = 0.041), shows exclusively interaction effects. The minor allele is significantly associated with decreased TAGs in individuals with fish oil supplementation, but with increased TAGs in those without supplementation. This locus is significantly associated with higher GJB2 expression of connexin 26 in adipose tissue; connexin activity is known to change upon exposure to omega-3 fatty acids. Significant interaction effects were also found in three other loci in the genes SLC12A3 (HDL-C), ABCA6 (LDL-C), and MLXIPL (LDL-C), but highly significant main effects are also present. Our study identifies novel gene-diet interaction effects for four genetic loci, whose effects on blood lipids are modified by fish oil supplementation. These findings highlight the need and possibility for personalized nutrition. Author summary: We utilized the unprecedentedly large genotype and phenotype dataset in the UK Biobank to perform a genome-wide association study (GWAS) which accounts for the interplay between genotype and dietary intake. We examined the interaction effects of fish oil supplementation on levels of blood lipids (LDL-C, HDL-C, TAGs, and total cholesterol). Our findings were replicated in the Atherosclerosis Risk in Communities (ARIC) Study. We found that at the genetic variant rs112803755 (A>G), the minor allele (G) is associated with a decrease in TAGs among individuals with fish oil supplementation, but is associated with an increase in TAGs among those without supplementation. In other words, only individuals carrying the minor allele benefit from fish oil supplementation in reducing TAG levels. We further analyzed rs112803755 with functional genomics data from the Genotype-Tissue Expression (GTEx) project to identify potential target genes, and found a connexin coding gene which has been previously reported to respond to cellular omega-3 levels. This research suggests that inter-personal variation in TAG response to fish oil supplementation is in part explained by genotype, and that fish oil dose adjustment based on genotype should be investigated as a means to protect against cardiovascular disease risk. [ABSTRACT FROM AUTHOR]