All organisms use fatty acids (FAs) for energy substrates and as precursors for membrane and signaling lipids. The most efficient way to transport and store FAs is in the form of triglycerides (TGs); ...however, TGs are not capable of traversing biological membranes and therefore need to be cleaved by TG hydrolases ("lipases") before moving in or out of cells. This biochemical process is generally called "lipolysis." Intravascular lipolysis degrades lipoprotein-associated TGs to FAs for their subsequent uptake by parenchymal cells, whereas intracellular lipolysis generates FAs and glycerol for their release (in the case of white adipose tissue) or use by cells (in the case of other tissues). Although the importance of lipolysis has been recognized for decades, many of the key proteins involved in lipolysis have been uncovered only recently. Important new developments include the discovery of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), the molecule that moves lipoprotein lipase from the interstitial spaces to the capillary lumen, and the discovery of adipose triglyceride lipase (ATGL) and comparative gene identification-58 (CGI-58) as crucial molecules in the hydrolysis of TGs within cells. This review summarizes current views of lipolysis and highlights the relevance of this process to human disease.
By synthesizing recent studies employing a wide range of approaches (modern observations, paleo reconstructions, and climate model simulations), this paper provides a comprehensive review of the ...linkage between multidecadal Atlantic Meridional Overturning Circulation (AMOC) variability and Atlantic Multidecadal Variability (AMV) and associated climate impacts. There is strong observational and modeling evidence that multidecadal AMOC variability is a crucial driver of the observed AMV and associated climate impacts and an important source of enhanced decadal predictability and prediction skill. The AMOC‐AMV linkage is consistent with observed key elements of AMV. Furthermore, this synthesis also points to a leading role of the AMOC in a range of AMV‐related climate phenomena having enormous societal and economic implications, for example, Intertropical Convergence Zone shifts; Sahel and Indian monsoons; Atlantic hurricanes; El Niño–Southern Oscillation; Pacific Decadal Variability; North Atlantic Oscillation; climate over Europe, North America, and Asia; Arctic sea ice and surface air temperature; and hemispheric‐scale surface temperature. Paleoclimate evidence indicates that a similar linkage between multidecadal AMOC variability and AMV and many associated climate impacts may also have existed in the preindustrial era, that AMV has enhanced multidecadal power significantly above a red noise background, and that AMV is not primarily driven by external forcing. The role of the AMOC in AMV and associated climate impacts has been underestimated in most state‐of‐the‐art climate models, posing significant challenges but also great opportunities for substantial future improvements in understanding and predicting AMV and associated climate impacts.
Key Points
There is strong evidence that multidecadal variability of the AMOC is a key driver of AMV and associated climate impacts
The AMOC‐AMV linkage is consistent with observed key elements of AMV, and it is important to use multivariate metrics to understand AMV
AMOC‐induced Atlantic meridional heat transport and net surface heat flux anomalies are crucial for many AMV‐related climate impacts
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Lipoprotein lipase (LPL), identified in the 1950s, has been studied intensively by biochemists, physiologists, and clinical investigators. These efforts uncovered a central role for LPL in plasma ...triglyceride metabolism and identified LPL mutations as a cause of hypertriglyceridemia. By the 1990s, with an outline for plasma triglyceride metabolism established, interest in triglyceride metabolism waned. In recent years, however, interest in plasma triglyceride metabolism has awakened, in part because of the discovery of new molecules governing triglyceride metabolism. One such protein—and the focus of this review—is GPIHBP1, a protein of capillary endothelial cells. GPIHBP1 is LPL’s essential partner: it binds LPL and transports it to the capillary lumen; it is essential for lipoprotein margination along capillaries, allowing lipolysis to proceed; and it preserves LPL’s structure and activity. Recently, GPIHBP1 was the key to solving the structure of LPL. These developments have transformed the models for intravascular triglyceride metabolism.
Young et al. review mechanisms for intravascular triglyceride metabolism, focusing on the role of GPIHBP1 in capturing lipoprotein lipase (LPL) within the subendothelial spaces, transporting LPL across endothelial cells to its site of action in the capillary lumen, stabilizing the structural integrity of LPL, and mediating lipoprotein margination along capillaries.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
We show that mice with a targeted deficiency in the gene encoding the lipogenic transcription factor SREBP-1a are resistant to endotoxic shock and systemic inflammatory response syndrome induced by ...cecal ligation and puncture (CLP). When macrophages from the mutant mice were challenged with bacterial lipopolysaccharide, they failed to activate lipogenesis as well as two hallmark inflammasome functions, activation of caspase-1 and secretion of IL-1β. We show that SREBP-1a activates not only genes required for lipogenesis in macrophages but also the gene encoding Nlrp1a, which is a core inflammasome component. Thus, SREBP-1a links lipid metabolism to the innate immune response, which supports our hypothesis that SREBPs evolved to regulate cellular reactions to external challenges that range from nutrient limitation and hypoxia to toxins and pathogens.
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► SREBP-1a-deficient mice are protected from toxic shock ► Macrophages from SREBP-1a-deficient mice have reduced inflammasome function ► SREBP-1a directly activates the gene for inflammasome subunit Nlrp1a in macrophages ► SREBP-1a stimulates lipogenesis in macrophages in response to LPS challenge
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Currently, there is no established guidance on how to process and evaluate resected lung cancer specimens after neoadjuvant therapy in the setting of clinical trials and clinical practice. There is ...also a lack of precise definitions on the degree of pathologic response, including major pathologic response or complete pathologic response. For other cancers such as osteosarcoma and colorectal, breast, and esophageal carcinomas, there have been multiple studies investigating pathologic assessment of the effects of neoadjuvant therapy, including some detailed recommendations on how to handle these specimens. A comprehensive mapping approach to gross and histologic processing of osteosarcomas after induction therapy has been used for over 40 years.
The purpose of this article is to outline detailed recommendations on how to process lung cancer resection specimens and to define pathologic response, including major pathologic response or complete pathologic response after neoadjuvant therapy. A standardized approach is recommended to assess the percentages of (1) viable tumor, (2) necrosis, and (3) stroma (including inflammation and fibrosis) with a total adding up to 100%. This is recommended for all systemic therapies, including chemotherapy, chemoradiation, molecular-targeted therapy, immunotherapy, or any future novel therapies yet to be discovered, whether administered alone or in combination. Specific issues may differ for certain therapies such as immunotherapy, but the grossing process should be similar, and the histologic evaluation should contain these basic elements. Standard pathologic response assessment should allow for comparisons between different therapies and correlations with disease-free survival and overall survival in ongoing and future trials. The International Association for the Study of Lung Cancer has an effort to collect such data from existing and future clinical trials. These recommendations are intended as guidance for clinical trials, although it is hoped they can be viewed as suggestion for good clinical practice outside of clinical trials, to improve consistency of pathologic assessment of treatment response.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Signaling pathways that promote adipose tissue thermogenesis are well characterized, but the limiters of energy expenditure are largely unknown. Here, we show that ablation of the anti-inflammatory ...cytokine IL-10 improves insulin sensitivity, protects against diet-induced obesity, and elicits the browning of white adipose tissue. Mechanistic studies define bone marrow cells as the source of the IL-10 signal and adipocytes as the target cell type mediating these effects. IL-10 receptor alpha is highly enriched in mature adipocytes and is induced in response to differentiation, obesity, and aging. Assay for transposase-accessible chromatin sequencing (ATAC-seq), ChIP-seq, and RNA-seq reveal that IL-10 represses the transcription of thermogenic genes in adipocytes by altering chromatin accessibility and inhibiting ATF and C/EBPβ recruitment to key enhancer regions. These findings expand our understanding of the relationship between inflammatory signaling pathways and adipose tissue function and provide insight into the physiological control of thermogenesis that could inform future therapy.
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•Mice lacking IL-10 have increased energy expenditure and adipose thermogenesis•IL-10 acts on IL-10Rα in adipose tissue to antagonize adrenergic tone•IL-10Rα knockdown promotes the browning of subcutaneous white adipose tissue•IL-10 affects chromatin structure and C/EBPβ and ATF occupancy at thermogenic genes
An anti-inflammatory cytokine suppresses adipocyte thermogenesis to limit energy expenditure.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Advances in gene editing are leading to new medical interventions where patients’ own cells are used for stem cell therapies and immunotherapies. One of the key limitations to translating these ...treatments to the clinic is the need for scalable technologies for engineering cells efficiently and safely. Toward this goal, microfluidic strategies to induce membrane pores and permeability have emerged as promising techniques to deliver biomolecular cargo into cells. As these technologies continue to mature, there is a need to achieve efficient, safe, nontoxic, fast, and economical processing of clinically relevant cell types. We demonstrate an acoustofluidic sonoporation method to deliver plasmids to immortalized and primary human cell types, based on pore formation and permeabilization of cell membranes with acoustic waves. This acoustofluidic-mediated approach achieves fast and efficient intracellular delivery of an enhanced green fluorescent protein-expressing plasmid to cells at a scalable throughput of 200,000 cells/min in a single channel. Analyses of intracellular delivery and nuclearmembrane rupture revealed mechanisms underlying acoustofluidic delivery and successful gene expression. Our studies show that acoustofluidic technologies are promising platforms for gene delivery and a useful tool for investigating membrane repair.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
LPL hydrolyzes triglycerides in triglyceride-rich lipoproteins along the capillaries of heart, skeletal muscle, and adipose tissue. The activity of LPL is repressed by angiopoietin-like 4 (ANGPTL4) ...but the underlying mechanisms have not been fully elucidated. Our objective was to study the cellular location and mechanism for LPL inhibition by ANGPTL4. We performed studies in transfected cells, ex vivo studies, and in vivo studies with Angptl4−/− mice. Cotransfection of CHO pgsA-745 cells with ANGPTL4 and LPL reduced intracellular LPL protein levels, suggesting that ANGPTL4 promotes LPL degradation. This conclusion was supported by studies of primary adipocytes and adipose tissue explants from wild-type and Angptl4−/− mice. Absence of ANGPTL4 resulted in accumulation of the mature-glycosylated form of LPL and increased secretion of LPL. Blocking endoplasmic reticulum (ER)-Golgi transport abolished differences in LPL abundance between wild-type and Angptl4−/− adipocytes, suggesting that ANGPTL4 acts upon LPL after LPL processing in the ER. Finally, physiological changes in adipose tissue ANGPTL4 expression during fasting and cold resulted in inverse changes in the amount of mature-glycosylated LPL in wild-type mice, but not Angptl4−/− mice. We conclude that ANGPTL4 promotes loss of intracellular LPL by stimulating LPL degradation after LPL processing in the ER.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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