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Journal ArticleDOI: 10.1016/J.CMET.2020.12.001

Lysosomal lipoprotein processing in endothelial cells stimulates adipose tissue thermogenic adaptation.

02 Mar 2021-Cell Metabolism (Elsevier)-Vol. 33, Iss: 3
Abstract: In response to cold exposure, thermogenic adipocytes internalize large amounts of fatty acids after lipoprotein lipase-mediated hydrolysis of triglyceride-rich lipoproteins (TRL) in the capillary lumen of brown adipose tissue (BAT) and white adipose tissue (WAT). Here, we show that in cold-exposed mice, vascular endothelial cells in adipose tissues endocytose substantial amounts of entire TRL particles. These lipoproteins subsequently follow the endosomal-lysosomal pathway, where they undergo lysosomal acid lipase (LAL)-mediated processing. Endothelial cell-specific LAL deficiency results in impaired thermogenic capacity as a consequence of reduced recruitment of brown and brite/beige adipocytes. Mechanistically, TRL processing by LAL induces proliferation of endothelial cells and adipocyte precursors via beta-oxidation-dependent production of reactive oxygen species, which in turn stimulates hypoxia-inducible factor-1α-dependent proliferative responses. In conclusion, this study demonstrates a physiological role for TRL particle uptake into BAT and WAT and establishes endothelial lipoprotein processing as an important determinant of adipose tissue remodeling during thermogenic adaptation.

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Topics: Adipose tissue (64%), White adipose tissue (64%), Brown adipose tissue (61%) ... read more
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7 results found


Journal ArticleDOI: 10.1038/S41568-021-00375-9
Abstract: Oncogenic mutations in KRAS drive common metabolic programmes that facilitate tumour survival, growth and immune evasion in colorectal carcinoma, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. However, the impacts of mutant KRAS signalling on malignant cell programmes and tumour properties are also dictated by tumour suppressor losses and physiological features specific to the cell and tissue of origin. Here we review convergent and disparate metabolic networks regulated by oncogenic mutant KRAS in colon, lung and pancreas tumours, with an emphasis on co-occurring mutations and the role of the tumour microenvironment. Furthermore, we explore how these networks can be exploited for therapeutic gain.

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Topics: KRAS (61%), Tumor microenvironment (53%)

13 Citations


Open accessJournal ArticleDOI: 10.1016/J.MOLMET.2021.101238
Joerg Heeren1, Ludger Scheja1Institutions (1)
Abstract: Background Non-alcoholic fatty liver disease, or as recently proposed ‘metabolic-associated fatty liver disease’ (MAFLD), is characterized by pathological accumulation of triglycerides and other lipids in hepatocytes. This common disease can progress from simple steatosis to steatohepatitis, and eventually end-stage liver diseases. MAFLD is closely related to disturbances in systemic energy metabolism, including insulin resistance and atherogenic dyslipidemia. Scope of review The liver is the central organ in lipid metabolism by secreting very low density lipoproteins (VLDL) and, on the other hand, by internalizing fatty acids and lipoproteins. This review article discusses recent research addressing hepatic lipid synthesis, VLDL production, and lipoprotein internalization as well as the lipid exchange between adipose tissue and the liver in the context of MAFLD. Major conclusions Liver steatosis in MAFLD is triggered by excessive hepatic triglyceride synthesis utilizing fatty acids derived from white adipose tissue (WAT), de novo lipogenesis (DNL) and endocytosed remnants of triglyceride-rich lipoproteins. In consequence of high hepatic lipid content, VLDL secretion is enhanced, which is the primary cause of complex dyslipidemia typical for subjects with MAFLD. Interventions reducing VLDL secretory capacity attenuate dyslipidemia while they exacerbate MAFLD, indicating that the balance of lipid storage versus secretion in hepatocytes is a critical parameter determining disease outcome. Proof of concept studies have shown that promoting lipid storage and energy combustion in adipose tissues reduces hepatic lipid load and thus ameliorates MAFLD. Moreover, hepatocellular triglyceride synthesis from DNL and WAT-derived fatty acids can be targeted to treat MAFLD. However, more research is needed to understand how individual transporters, enzymes, and their isoforms affect steatosis and dyslipidemia in vivo, and whether these two aspects of MAFLD can be selectively treated. Processing of cholesterol-enriched lipoproteins appears less important for steatosis. It may, however, modulate inflammation and consequently MAFLD progression.

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Topics: Fatty liver (68%), Steatohepatitis (66%), Steatosis (62%) ... read more

12 Citations


Journal ArticleDOI: 10.1038/S42255-021-00417-4
01 Jun 2021-
Abstract: The perception of adipose tissue, both in the scientific community and in the general population, has changed dramatically in the past 20 years. While adipose tissue was thought for a long time to be a rather simple lipid storage entity, it is now recognized as a highly heterogeneous organ and a critical regulator of systemic metabolism, composed of many different subtypes of cells, with important endocrine functions. Additionally, adipose tissue is nowadays recognized to contribute to energy turnover, due to the presence of specialized thermogenic adipocytes, which can be found in many adipose depots. This review discusses the unprecedented insights that we have gained into the heterogeneity of thermogenic adipocytes and their respective precursors due to the technical developments in single-cell and nucleus technologies. These methodological advances have increased our understanding of how adipose tissue catabolic function is influenced by developmental and intercellular communication events. Adipose tissue has emerged as a highly heterogeneous organ. Sun et al. discuss the heterogeneity of thermogenic adipocytes and their precursors, highlighting the single-cell technologies that help to characterize adipose tissues in depth.

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Topics: Adipose tissue (66%), Population (51%)

3 Citations


Open accessJournal ArticleDOI: 10.3390/IJMS22115906
Abstract: The concerning worldwide increase of obesity and chronic metabolic diseases, such as T2D, dyslipidemia, and cardiovascular disease, motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there has been growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat, as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Furthermore, we discuss the alterations in brown and beige adipose tissue function during obesity and explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.

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Topics: Adipose tissue (51%), Thermogenesis (50%)

3 Citations


Open accessJournal ArticleDOI: 10.1007/S11010-020-04004-1
Kezhen Yi1, Yuan Rong1, Cheng Wang2, Lanxiang Huang1  +1 moreInstitutions (2)
Abstract: SARS-CoV-2 is one of the beta-coronaviruses with the spike protein. It invades host cells by binding to angiotensin converting enzyme 2 (ACE2). This newly discovered virus can result in excessive inflammation and immune pathological damage, as shown by a decreased number of peripheral lymphocytes, increased levels of cytokines, and damages of lung, heart, liver, kidney, and other organs. Effective therapeutic modalities such as new antiviral drugs and vaccines against this emerging virus need to be thoroughly studied and developed. However, so far the only recognized but mild progress in this area is the screening of old drugs for new uses. Therefore, rapid and accurate laboratory SARS-CoV-2 testing approaches are the important basis of identification and blockage of COVID-19 transmission. For COVID-19 patients with different clinical classifications (mild, common, severe, and critically severe), dynamic monitoring of functional indicators of susceptible and vital organs is an important strategy for evaluating therapeutic efficacy and prognosis. In this review, we summarized SARS-CoV-2 laboratory diagnostic schemes, pathophysiological indices of tissues and organs of COVID-19 patients, and laboratory diagnostic strategies for distinct disease stages. Further, we discussed the importance of hierarchical management and dynamic observation in SARS-CoV-2 laboratory diagnostics. We then summed up the advance in SARS-CoV-2 testing technology and described the prospect of intelligent medicine in the prevention of infectious disease outbreaks.

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2 Citations


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95 results found


Journal ArticleDOI: 10.1152/PHYSREV.00015.2003
Barbara Cannon1, Jan Nedergaard1Institutions (1)
Abstract: Cannon, Barbara, and Jan Nedergaard. Brown Adipose Tissue: Function and Physiological Significance. Physiol Rev 84: 277–359, 2004; 10.1152/physrev.00015.2003.—The function of brown adipose tissue i...

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Topics: White adipose tissue (70%), Brown adipose tissue (67%), Adipose tissue (66%) ... read more

4,872 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2019.05.031
13 Jun 2019-Cell
Abstract: Single-cell transcriptomics has transformed our ability to characterize cell states, but deep biological understanding requires more than a taxonomic listing of clusters. As new methods arise to measure distinct cellular modalities, a key analytical challenge is to integrate these datasets to better understand cellular identity and function. Here, we develop a strategy to "anchor" diverse datasets together, enabling us to integrate single-cell measurements not only across scRNA-seq technologies, but also across different modalities. After demonstrating improvement over existing methods for integrating scRNA-seq data, we anchor scRNA-seq experiments with scATAC-seq to explore chromatin differences in closely related interneuron subsets and project protein expression measurements onto a bone marrow atlas to characterize lymphocyte populations. Lastly, we harmonize in situ gene expression and scRNA-seq datasets, allowing transcriptome-wide imputation of spatial gene expression patterns. Our work presents a strategy for the assembly of harmonized references and transfer of information across datasets.

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3,853 Citations


Open accessJournal ArticleDOI: 10.1042/BJ20031253
Abstract: Non-phagocytic eukaryotic cells can internalize particles <1 microm in size, encompassing pathogens, liposomes for drug delivery or lipoplexes applied in gene delivery. In the present study, we have investigated the effect of particle size on the pathway of entry and subsequent intracellular fate in non-phagocytic B16 cells, using a range of fluorescent latex beads of defined sizes (50-1000 nm). Our data reveal that particles as large as 500 nm were internalized by cells via an energy-dependent process. With an increase in size (50-500 nm), cholesterol depletion increased the efficiency of inhibition of uptake. The processing of the smaller particles was significantly perturbed upon microtubule disruption, while displaying a negligible effect on that of the 500 nm beads. Inhibitor and co-localization studies revealed that the mechanism by which the beads were internalized, and their subsequent intracellular routing, was strongly dependent on particle size. Internalization of microspheres with a diameter <200 nm involved clathrin-coated pits. With increasing size, a shift to a mechanism that relied on caveolae-mediated internalization became apparent, which became the predominant pathway of entry for particles of 500 nm in size. At these conditions, delivery to the lysosomes was no longer apparent. The data indicate that the size itself of (ligand-devoid) particles can determine the pathway of entry. The clathrin-mediated pathway of endocytosis shows an upper size limit for internalization of approx. 200 nm, and kinetic parameters may determine the almost exclusive internalization of such particles along this pathway rather than via caveolae.

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Topics: Internalization (60%), Particle size (53%), Endosome (53%) ... read more

2,415 Citations


Open accessJournal ArticleDOI: 10.1016/J.CELL.2012.05.016
Jun Wu1, Pontus Boström1, Lauren M. Sparks2, Li Ye1  +13 moreInstitutions (4)
20 Jul 2012-Cell
Abstract: Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of "beige" cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential. PAPERCLIP:

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Topics: PRDM16 (60%), FNDC5 (58%), Brown adipose tissue (55%) ... read more

2,409 Citations


Open accessJournal ArticleDOI: 10.1128/MCB.12.12.5447
Gregg L. Semenza1, Guang L. Wang1Institutions (1)
Abstract: We have identified a 50-nucleotide enhancer from the human erythropoietin gene 3'-flanking sequence which can mediate a sevenfold transcriptional induction in response to hypoxia when cloned 3' to a simian virus 40 promoter-chloramphenicol acetyltransferase reporter gene and transiently expressed in Hep3B cells Nucleotides (nt) 1 to 33 of this sequence mediate sevenfold induction of reporter gene expression when present in two tandem copies compared with threefold induction when present in a single copy, suggesting that nt 34 to 50 bind a factor which amplifies the induction signal DNase I footprinting demonstrated binding of a constitutive nuclear factor to nt 26 to 48 Mutagenesis studies revealed that nt 4 to 12 and 19 to 23 are essential for induction, as substitutions at either site eliminated hypoxia-induced expression Electrophoretic mobility shift assays identified a nuclear factor which bound to a probe spanning nt 1 to 18 but not to a probe containing a mutation which eliminated enhancer function Factor binding was induced by hypoxia, and its induction was sensitive to cycloheximide treatment We have thus defined a functionally tripartite, 50-nt hypoxia-inducible enhancer which binds several nuclear factors, one of which is induced by hypoxia via de novo protein synthesis

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Topics: Enhancer (57%), Transcription factor (55%), Reporter gene (55%) ... read more

2,370 Citations