Regulation of triglyceride-rich lipoprotein (TGRL) metabolism. Serum triglyceride concentration identifies the presence of potentially atherogenic TGRLs. Human genetics strongly support remnants of ...TGRLs as a causal cardiovascular risk factor. Remnants of TGRLs play a role in residual risk on statin therapy. Apo: apolipoprotein; ANGPTL: angiopoietin-like protein; LPL: lipoprotein lipase; RLP: remnant lipoprotein.▪
Low-density lipoprotein cholesterol is a well-known causal factor for atherosclerotic cardiovascular disease, and is the primary target of lipid-lowering therapy. There is, however, still a substantial risk of atherosclerotic cardiovascular disease events despite intensive statin therapy, and data from clinical trials suggest that an elevated concentration of triglycerides is a marker of residual cardiovascular risk on low-density lipoprotein-lowering therapy. Serum triglycerides are a biomarker for triglyceride-rich lipoproteins, and several lines of evidence indicate that triglyceride-rich lipoproteins and their cholesterol-enriched remnant particles are associated with atherogenesis. Moreover, genetic data in humans strongly suggest that the remnants of triglyceride-rich lipoproteins are a causal cardiovascular risk factor. Although lifestyle changes remain the cornerstone of management of hypertriglyceridaemia, a recent trial with high doses of the omega-3 fatty acid icosapent ethyl showed a significant reduction in cardiovascular events that was not explained by the reduction in triglycerides alone. In patients with elevated triglycerides, several novel drugs are in development to reduce the residual risk on statin therapy linked to an excess of atherogenic triglyceride-rich lipoproteins. In this review, we provide an update on the biology, epidemiology and genetics of triglycerides, and the risk of atherosclerotic cardiovascular disease.
Le cholestérol des lipoprotéines de basse densité est un facteur causal bien reconnu des maladies cardiovasculaires liées à l’athérosclérose et c’est l’objectif primaire d’un traitement hypolipémiant. Toutefois un risque substantiel persiste malgré un traitement par statine de forte intensité et des données récentes d’essais cliniques suggèrent qu’une élévation des triglycérides est un marqueur du risque cardiovasculaire résiduel sous traitement abaissant les lipoprotéines de basse densité. Les triglycérides sériques sont un biomarqueur des lipoprotéines riches en triglycérides et de nombreuses preuves indiquent que les lipoprotéines riches en triglycérides et leurs résidus d’hydrolyse (ou remnants) enrichis en cholestérol participent à l’athérogénèse. De plus des études génétiques supportent fortement un rôle causal des remnants dans le risque cardiovasculaire. Bien que les mesures hygiéno-diététiques restent la pierre angulaire de la prise en charge d’une hypertriglycéridémie, une étude clinique récente utilisant de fortes doses d’un acide gras omega-3, l’icosapent ethyl, a montré une réduction significative des évènements cardiovasculaires, inexpliquée par la seule baisse des triglycérides. Chez des patients avec élévation des triglycérides sous traitement par statine, plusieurs nouvelles approches thérapeutiques sont en développement pour réduire le risque résiduel lié à l’excès de lipoprotéines riches en triglycérides. Cette revue propose une mise à jour des données biologiques, épidémiologiques et génétiques des relations entre triglycérides et risque de maladies cardiovasculaires liées à l’athérosclérose.
About 20 global climate models have been run for the Intergovernmental Panel on Climate Change (IPCC) Fourth Assessment Report (AR4) to predict climate change due to anthropogenic activities. ...Evaluating these models is an important step to establish confidence in climate projections. Model evaluation, however, is often performed on a gridpoint basis despite the fact that models are known to often be unreliable at such small spatial scales. In this study, the annual mean values of surface air temperature and precipitation are analyzed. Using a spatial smoothing technique with a variable-scale parameter it is shown that the intermodel spread, as well as model errors from observations, is reduced as the characteristic smoothing scale increases. At the same time, the ability to reproduce small-scale features is reduced and the simulated patterns become fuzzy. Depending on the variable of interest, the location, and the way that data are aggregated, different optimal smoothing scales from the gridpoint size to about 2000 km are found to give good agreement with present-day observation yet retain most regional features of the climate signal. Higher model resolution surprisingly does not imply much better agreement with temperature observations, in particular with stronger smoothing, and resolving smaller scales therefore does not necessarily seem to improve the simulation of large-scale climate features. Similarities in mean temperature and precipitation fields for a pair of models in the ensemble persist locally for about a century into the future, providing some justification for subtracting control errors in the models. Large-scale to global errors, however, are not well preserved over time, consistent with a poor constraint of the present-day climate on the simulated global temperature and precipitation response.
Among the pathways involved in the regulation of macrophage functions, the metabolism of unsaturated fatty acids is central. Indeed, unsaturated fatty acids act as precursors of bioactive molecules ...such as prostaglandins, leukotrienes, resolvins and related compounds. As components of phospholipids, they have a pivotal role in cell biology by regulating membrane fluidity and membrane-associated cellular processes. Finally, polyunsaturated fatty acids (PUFAs) are also endowed with ligand properties for numerous membrane or nuclear receptors. Although myeloid cells are dependent on the metabolic context for the uptake of essential FAs, recent studies showed that these cells autonomously handle the synthesis of n-3 and n-6 long chain PUFAs such as arachidonic acid and eicosapentaenoic acid. Moreover, targeting PUFA metabolism in macrophages influences pathological processes, including atherosclerosis, by modulating macrophage functions. Omics evidence also supports a role for macrophage PUFA metabolism in the development of cardiometabolic diseases in humans.
Currently, there is a renewed interest in the role of n-3/n-6 PUFAs and their oxygenated derivatives in the onset of atherosclerosis and plaque rupture. Purified n-3 FA supplementation appears as a potential strategy in the treatment and prevention of cardiovascular diseases. In this context, the ability of immune cells to handle and to synthesize very long chain PUFA must absolutely be integrated and better understood.
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•The metabolism of polyunsaturated fatty acids (PUFAs) is central in the regulation of macrophage functions.•Macrophages autonomously regulate the synthesis of PUFAs and their incorporation in phospholipids and other cellular lipids.•Genetic alteration of unsaturated FA metabolism influences atherosclerosis, by modulating macrophage functions.
HIF-1α exerts both detrimental and beneficial actions in atherosclerosis. While there is evidence that HIF-1α could be pro-atherogenic within the atheromatous plaque, experimental models of ...atherosclerosis suggest a more complex role that depends on the cell type expressing HIF-1α. In atheroma plaques, HIF-1α is stabilized by local hypoxic conditions and by the lipid microenvironment. Macrophage exposure to oxidized LDLs (oxLDLs) or to necrotic plaque debris enriched with oxysterols induces HIF-1α -dependent pathways. Moreover, HIF-1α is involved in many oxLDL-induced effects in macrophages including inflammatory response, angiogenesis and metabolic reprogramming. OxLDLs activate toll-like receptor signaling pathways to promote HIF-1α stabilization. OxLDLs and oxysterols also induce NADPH oxidases and reactive oxygen species production, which subsequently leads to HIF-1α stabilization. Finally, recent investigations revealed that the activation of liver X receptor, an oxysterol nuclear receptor, results in an increase in HIF-1α transcriptional activity. Reciprocally, HIF-1α signaling promotes triglycerides and cholesterol accumulation in macrophages. Hypoxia and HIF-1α increase the uptake of oxLDLs, promote cholesterol and triglyceride synthesis and decrease cholesterol efflux. In conclusion, the impact of HIF-1α on cholesterol homeostasis within macrophages and the feedback activation of the inflammatory response by oxysterols
HIF-1α could play a deleterious role in atherosclerosis. In this context, studies aimed at understanding the specific mechanisms leading to HIF-1α activation within the plaque represents a promising field for research investigations and a path toward development of novel therapies.
ABSTRACT
Studying long‐term variations and trends in grid datasets is often complicated by variations in the station network used for spatial interpolation. The increase in station density over time ...gives rise to inhomogeneities in the datasets. Here we introduce a gridded dataset of monthly precipitation for the entire Alpine region with a grid‐spacing of 5 km that extends over more than 100 years (1901–2008), is largely unaffected by network variations and still exploits information from recent dense observations. It is derived by a reconstruction procedure that combines data from several thousand stations over recent decades with long‐term and almost continuous station series at much coarser resolution (120 stations). Our dataset is a recalculation and update of a previous and similarly constructed dataset that ended in 1990. The reconstruction method is modified for the present application and an entirely new high‐resolution reference was used for calibration. The reconstruction explains more than 80% of the month‐by‐month variance in Switzerland and Austria where the long‐term station network is comparatively denser. We also demonstrate that the reconstruction can effectively filter out artifacts in trend patterns due to local inhomogeneities in the data and the station network. Precipitation trends calculated with the updated grid dataset are qualitatively similar with those found previously, but statistical significance has partly changed. A likely reason for these discrepancies is decadal variations, notably in winter, and this calls for prudence in the interpretation of trend results from conventional tests.
Computed tomography remains strongly underused in plant sciences despite its high potential in delivering detailed 3D phenotypical information because of the low X-ray absorption of most plant ...tissues. Existing protocols to study soft tissues display poor performance, especially when compared to those used on animals. More efficient protocols to study plant material are therefore needed. Flowers of Arabidopsis thaliana and Marcgravia caudata were immersed in a selection of contrasting agents used to treat samples for transmission electron microscopy. Grayscale values for floral tissues and background were measured as a function of time. Contrast was quantified via a contrast index. The thick buds of Marcgravia were scanned to determine which contrasting agents best penetrate thick tissues. The highest contrast increase with cytoplasm-rich tissues was obtained with phosphotungstate, whereas osmium tetroxide and bismuth tatrate displayed the highest contrast increase with vacuolated tissues. Phosphotungstate also displayed the best sample penetration. Furthermore, infiltration with phosphotungstate allowed imaging of all plants parts at a high resolution of 3 µm, which approaches the maximum resolution of our equipment: 1.5 µm. The high affinity of phosphotungstate for vasculature, cytoplasm-rich tissue, and pollen causes these tissues to absorb more X-rays than the surrounding tissues, which, in turn, makes these tissues appear brighter on the scan data. Tissues with different brightness can then be virtually dissected from each other by selecting the bracket of grayscale to be visualized. Promising directions for the future include in silico phenotyping and developmental studies of plant inner parts (e.g., ovules, vasculature, pollen, and cell nuclei) via virtual dissection as well as correlations of quantitative phenotypes with omics datasets. Therefore, this work represents a crucial improvement of previous methods, allowing new directions of research to be undertaken in areas ranging from morphology to systems biology.
Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis, but its contribution to macrophage functions and host defense remains to be ...delineated. Here, we showed that lipopolysaccharide (LPS) in combination with IFN-γ inhibited PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggered classical macrophage activation in a mitochondrial ROS-dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation, which favored bactericidal clearance and led to a better survival rate. Reciprocally, mitochondrial uncouplers that promote mitophagy reversed LPS/IFN-γ-mediated activation of macrophages and led to immunoparalysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy was inhibited in blood monocytes of patients with sepsis as compared with nonseptic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.
Apolipoprotein C1 (apoC1) is a small size apolipoprotein whose exact role is not totally clarified but which seems to modulate significantly the metabolism of lipoproteins. ApoC1 is involved in the ...metabolism of triglyceride-rich lipoproteins by inhibiting the binding of very low density lipoproteins (VLDL) to VLDL-receptor (VLDL-R), to low density lipoprotein receptor (LDL-R) and to LDL receptor related protein (LRP), by reducing the activity of lipoprotein lipase (LPL) and by stimulating VLDL production, all these effects leading to increase plasma triglycerides. ApoC1 takes also part in the metabolism of high density lipoproteins (HDL) by inhibiting Cholesterol Ester Transfer Protein (CETP). The functionality of apoC1 on CETP activity is impaired in diabetes that might account, at least in part, for the increased plasma CETP activity observed in patients with diabetes. Its different effects on lipoprotein metabolism with a possible role in the modulation of inflammation makes the net impact of apoC1 on cardiometabolic risk difficult to figure out and apoC1 might be considered as pro-atherogenic or anti-atherogenic depending on the overall metabolic context. Making the link between total plasma apoC1 levels and the risk of cardio-metabolic diseases is difficult due to the high exchangeability of this small protein whose biological effects might depend essentially on its association with VLDL or HDL. The role of apoC1 in humans is not entirely elucidated and further studies are needed to determine its precise role in lipid metabolism and its possible pleiotropic effects on inflammation and vascular wall biology. In this review, we will present data on apoC1 structure and distribution among lipoproteins, on the effects of apoC1 on VLDL metabolism and HDL metabolism and we will discuss the possible links between apoC1, atherosclerosis and diabetes.
Although Th17 cells are known to promote tissue inflammation and autoimmunity, their role during cancer progression remains elusive. Here, we showed that in vitro Th17 cells generated with the ...cytokines IL-6 and TGF-β expressed CD39 and CD73 ectonucleotidases, leading to adenosine release and the subsequent suppression of CD4+ and CD8+ T cell effector functions. The IL-6-mediated activation of the transcription factor Stat3 and the TGF-β-driven downregulation of Gfi-1 transcription factor were both essential for the expression of ectonucleotidases during Th17 cell differentiation. Stat3 supported whereas Gfi-1 repressed CD39 and CD73 expression by binding to their promoters. Accordingly, Th17 cells differentiated with IL-1β, IL-6, and IL-23 but without TGF-β did not express ectonucleotidases and were not immunosuppressive. Finally, adoptive transfer of Th17 cells induced by TGF-β and IL-6 promoted tumor growth in a CD39-dependent manner. Thus, ectonucleotidase expression supports the immunosuppressive fate of Th17 cells in cancer.
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► Th17 cells express CD39 and CD73 ectonucleotidases ► Ectonucleotidase expression is transcriptionally regulated by STAT3 and GFI-1 ► Ectonucleotidase expression determines inflammatory vs suppressive fate of Th17 cells
Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has ...constituted a limitation to the clinical development of pharmacological LXR agonists. However, recent studies provided a different perspective. Beyond the quantitative accumulation of FA, it appears that LXRs induce qualitative changes in the FA profile and in the distribution of FAs among cellular lipid species. Thus, LXRs activate the production of polyunsaturated fatty acids (PUFAs) and their distribution into phospholipids via the control of FA desaturases, FA elongases, lysophosphatidylcholine acyltransferase (LPCAT3), and phospholipid transfer protein (PLTP). Therefore, LXRs control, in a dynamic manner, the PUFA composition and the physicochemical properties of cell membranes as well as the release of PUFA-derived lipid mediators. Recent studies suggest that modulation of PUFA and phospholipid metabolism by LXRs are involved in the control of lipogenesis and lipoprotein secretion by the liver. In myeloid cells, the interplay between LXR and PUFA metabolism affects the inflammatory response. Revisiting the complex role of LXRs in FA metabolism may open new opportunities for the development of LXR modulators in the field of cardiometabolic diseases.
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