21 research outputs found
Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation
Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. Conclusion: Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes.UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. beta-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFN gamma and 114 secretion).Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue.Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes
Adipocytes harbor a glucosylceramide biosynthesis pathway involved in iNKT cell activation
Background: Natural killer T (NKT) cells in adipose tissue (AT) contribute to whole body energy homeostasis. Results: Inhibition of the glucosylceramide synthesis in adipocytes impairs iNKT cell activity. Conclusion: Glucosylceramide biosynthesis pathway is important for endogenous lipid antigen activation of iNKT cells in adipocytes.Significance: Unraveling adipocyte-iNKT cell communication may help to fight obesity-induced AT dysfunction.Overproduction and/or accumulation of ceramide and ceramide metabolites, including glucosylceramides, can lead to insulin resistance. However, glucosylceramides also fulfill important physiological functions. They are presented by antigen presenting cells (APC) as endogenous lipid antigens via CD1d to activate a unique lymphocyte subspecies, the CD1d-restricted invariant (i) natural killer T (NKT) cells. Recently, adipocytes have emerged as lipid APC that can activate adipose tissue-resident iNKT cells and thereby contribute to whole body energy homeostasis. Here we investigate the role of the glucosylceramide biosynthesis pathway in the activation of iNKT cells by adipocytes.UDP-glucose ceramide glucosyltransferase (Ugcg), the first rate limiting step in the glucosylceramide biosynthesis pathway, was inhibited via chemical compounds and shRNA knockdown in vivo and in vitro. beta-1,4-Galactosyltransferase (B4Galt) 5 and 6, enzymes that convert glucosylceramides into potentially inactive lactosylceramides, were subjected to shRNA knock down. Subsequently, (pre)adipocyte cell lines were tested in co-culture experiments with iNKT cells (IFN gamma and 114 secretion).Inhibition of Ugcg activity shows that it regulates presentation of a considerable fraction of lipid self-antigens in adipocytes. Furthermore, reduced expression levels of either B4Galt5 or -6, indicate that B4Galt5 is dominant in the production of cellular lactosylceramides, but that inhibition of either enzyme results in increased iNKT cell activation. Additionally, in vivo inhibition of Ugcg by the aminosugar AMP-DNM results in decreased iNKT cell effector function in adipose tissue.Inhibition of endogenous glucosylceramide production results in decreased iNKT cells activity and cytokine production, underscoring the role of this biosynthetic pathway in lipid self-antigen presentation by adipocytes
The DNAJB6 and DNAJB8 Protein Chaperones Prevent Intracellular Aggregation of Polyglutamine Peptides
Bio-organic Synthesi
Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10
Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation
Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells
Invariant natural killer T (iNKT) cells act at the interface between lipid metabolism and immunity because of their restriction to lipid antigens presented on CD1d by antigen-presenting cells (APCs). How foreign lipid antigens are delivered to APCs remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time to our knowledge, stable complex formation of lipid antigens alpha-galactosylceramide (alpha GalCer), isoglobotrihexosylceramide, and OCH, a sphingosine-truncated analog of alpha GalCer, with VLDL and/or LDL in vitro and in vivo. We demonstrate LDL receptor-mediated (LDLR-mediated) uptake of lipoprotein-alpha GalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a potentially novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins.Metabolic health: pathophysiological trajectories and therap
Adipose tissue as an immunological organ Implications for childhood obesity
Obesity is increasingly considered as an inflammatory disorder. In adults, obesity induces inflammation of adipose tissue (AT). Through the release of inflammatory lipids and immune mediating proteins called adipokines, AT inflammation spreads to other tissues ranging from liver and muscle to the cardiovascular system and circulating immune cells, and drives low-grade systemic inflammation. The low-grade systemic inflammation provides a pivotal link between obesity and its metabolic and cardiovascular sequelae. In a recent Diabetologia paper, we showed that already in obese children, adipose tissue (AT) inflammation occurs (1). Interestingly, the severity of AT inflammation correlates with clinical parameters for insulin resistance. Furthermore, we showed that AT inflammation in childhood obesity drives low-grade systemic inflammation, and affects circulating immune cells such as monocytes, which are known to be involved in the development of atherosclerosis later in life. Taken together, our results suggest that modulating AT inflammation in childhood obesity provides a novel avenue for the prevention of long-term metabolic and cardiovascular disease. Next, we discovered a novel pathway to modulate AT inflammation. As recently published in JCI (2), we showed that AT-resident immune cells such as invariant natural killer T (iNKT) cells play a pivotal role in maintaining healthy adipose tissue. Through direct interplay with lipid-presenting adipocytes, iNKT cells suppress AT inflammation, and prevent systemic inflammation and insulin resistance in mice and humans. Knockout or antibody-mediated depletion of iNKT cells in mice has a devastating impact on AT inflammation and insulin resistance, while ligand-mediated stimulation of iNKT cells prevents metabolic derailment in obesity. Summarizing, our results show that modulation of iNKT cell function may prevent metabolic and cardiovascular complications in obese patients, including children. In conclusion, considering childhood obesity as an inflammatory disorder offers a novel perspective on the prevention of long-term metabolic and cardiovascular complications. Immune modulatory interventions show promise for the near-future, though their safety, cost-effectiveness and implementation in the integrative treatment of childhood obesity require careful consideratio
Kinetic studies on the carboxylation of 6-amino-penicillanic acid to 8-hydroxy-penillic acid
Potential of novel desert microalgae and cyanobacteria for commercial applications and CO2 sequestration
CO2 fixation by phototrophic microalgae and cyanobacteria is seen as a possible global carbon emissions reducer; however, novel microalgae and cyanobacterial strains with tolerance to elevated temperatures and CO2 concentrations are essential for further development of algae-based carbon capture. Four novel strains isolated from the Arabian Gulf were investigated for their thermotolerance and CO2-tolerance, as well as their carbon capture capability. Two strains, Leptolyngbya sp. and Picochlorum sp., grew well at 40 °C, with productivities of 106.6 ± 10.0 and 87.5 ± 2.1 mg biomass L−1 d−1, respectively. Tetraselmis sp. isolate showed the highest biomass productivity and carbon capture rate of 157.7 ± 10.3 mg biomass L−1 d−1 and 270.8 ± 23.9 mg CO2 L−1 d−1, respectively, both at 30 °C. Under 20% CO2, the biomass productivity increased over 2-fold for both Tetraselmis and Picochlorum isolates, to 333.8 ± 41.1 and 244.7 ± 29.5 mg biomass L−1 d−1. These two isolates also presented significant amounts of lipids, up to 25.6 ± 0.9% and 28.0 ± 2.0% (w/w), as well as presence of EPA and DHA. Picochlorum sp. was found to have a suitable FAME profile for biodiesel production. Both Tetraselmis and Picochlorum isolates showed promising characteristics, making them valuable strains for further investigation towards commercial applications and CO2 capture
Effects of fiber on placenta (A) and fetal liver (B) structure (Magnification ×200).
<p>C, control group; HF, high-fat and high-fiber group; SB, high-fat and sodium butyrate group; CHC, HF diet with CHC injection group.</p
Potential of novel desert microalgae and cyanobacteria for commercial applications and CO2 sequestration
CO2 fixation by phototrophic microalgae and cyanobacteria is seen as a possible global carbon emissions reducer; however, novel microalgae and cyanobacterial strains with tolerance to elevated temperatures and CO2 concentrations are essential for further development of algae-based carbon capture. Four novel strains isolated from the Arabian Gulf were investigated for their thermotolerance and CO2-tolerance, as well as their carbon capture capability. Two strains, Leptolyngbya sp. and Picochlorum sp., grew well at 40 °C, with productivities of 106.6 ± 10.0 and 87.5 ± 2.1 mg biomass L−1 d−1, respectively. Tetraselmis sp. isolate showed the highest biomass productivity and carbon capture rate of 157.7 ± 10.3 mg biomass L−1 d−1 and 270.8 ± 23.9 mg CO2 L−1 d−1, respectively, both at 30 °C. Under 20% CO2, the biomass productivity increased over 2-fold for both Tetraselmis and Picochlorum isolates, to 333.8 ± 41.1 and 244.7 ± 29.5 mg biomass L−1 d−1. These two isolates also presented significant amounts of lipids, up to 25.6 ± 0.9% and 28.0 ± 2.0% (w/w), as well as presence of EPA and DHA. Picochlorum sp. was found to have a suitable FAME profile for biodiesel production. Both Tetraselmis and Picochlorum isolates showed promising characteristics, making them valuable strains for further investigation towards commercial applications and CO2 capture