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Cell Metabolism

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https://www.readbyqxmd.com/read/29779826/the-bckdh-kinase-and-phosphatase-integrate-bcaa-and-lipid-metabolism-via-regulation-of-atp-citrate-lyase
#1
Phillip J White, Robert W McGarrah, Paul A Grimsrud, Shih-Chia Tso, Wen-Hsuan Yang, Jonathan M Haldeman, Thomas Grenier-Larouche, Jie An, Amanda L Lapworth, Inna Astapova, Sarah A Hannou, Tabitha George, Michelle Arlotto, Lyra B Olson, Michelle Lai, Guo-Fang Zhang, Olga Ilkayeva, Mark A Herman, R Max Wynn, David T Chuang, Christopher B Newgard
Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K...
May 11, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29754952/early-time-restricted-feeding-improves-insulin-sensitivity-blood-pressure-and-oxidative-stress-even-without-weight-loss-in-men-with-prediabetes
#2
Elizabeth F Sutton, Robbie Beyl, Kate S Early, William T Cefalu, Eric Ravussin, Courtney M Peterson
Intermittent fasting (IF) improves cardiometabolic health; however, it is unknown whether these effects are due solely to weight loss. We conducted the first supervised controlled feeding trial to test whether IF has benefits independent of weight loss by feeding participants enough food to maintain their weight. Our proof-of-concept study also constitutes the first trial of early time-restricted feeding (eTRF), a form of IF that involves eating early in the day to be in alignment with circadian rhythms in metabolism...
May 8, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29754954/the-polycomb-dependent-epigenome-controls-%C3%AE-cell-dysfunction-dedifferentiation-and-diabetes
#3
Tess Tsai-Hsiu Lu, Steffen Heyne, Erez Dror, Eduard Casas, Laura Leonhardt, Thorina Boenke, Chih-Hsiang Yang, Sagar, Laura Arrigoni, Kevin Dalgaard, Raffaele Teperino, Lennart Enders, Madhan Selvaraj, Marius Ruf, Sunil J Raja, Huafeng Xie, Ulrike Boenisch, Stuart H Orkin, Francis C Lynn, Brad G Hoffman, Dominic Grün, Tanya Vavouri, Adelheid M Lempradl, J Andrew Pospisilik
To date, it remains largely unclear to what extent chromatin machinery contributes to the susceptibility and progression of complex diseases. Here, we combine deep epigenome mapping with single-cell transcriptomics to mine for evidence of chromatin dysregulation in type 2 diabetes. We find two chromatin-state signatures that track β cell dysfunction in mice and humans: ectopic activation of bivalent Polycomb-silenced domains and loss of expression at an epigenomically unique class of lineage-defining genes...
May 4, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29754953/arginase-2-suppresses-renal-carcinoma-progression-via-biosynthetic-cofactor-pyridoxal-phosphate-depletion-and-increased-polyamine-toxicity
#4
Joshua D Ochocki, Sanika Khare, Markus Hess, Daniel Ackerman, Bo Qiu, Jennie I Daisak, Andrew J Worth, Nan Lin, Pearl Lee, Hong Xie, Bo Li, Bradley Wubbenhorst, Tobi G Maguire, Katherine L Nathanson, James C Alwine, Ian A Blair, Itzhak Nissim, Brian Keith, M Celeste Simon
Kidney cancer, one of the ten most prevalent malignancies in the world, has exhibited increased incidence over the last decade. The most common subtype is "clear cell" renal cell carcinoma (ccRCC), which features consistent metabolic abnormalities, such as highly elevated glycogen and lipid deposition. By integrating metabolomics, genomic, and transcriptomic data, we determined that enzymes in multiple metabolic pathways are universally depleted in human ccRCC tumors, which are otherwise genetically heterogeneous...
May 4, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29731416/interleukin-6-delays-gastric-emptying-in-humans-with-direct-effects-on-glycemic-control
#5
Louise Lang Lehrskov, Mark Preben Lyngbaek, Line Soederlund, Grit Elster Legaard, Jan Adam Ehses, Sarah Elizabeth Heywood, Nicolai Jacob Wewer Albrechtsen, Jens Juul Holst, Kristian Karstoft, Bente Klarlund Pedersen, Helga Ellingsgaard
Gastric emptying is a critical regulator of postprandial glucose and delayed gastric emptying is an important mechanism of improved glycemic control achieved by short-acting glucagon-like peptide-1 (GLP-1) analogs in clinical practice. Here we report on a novel regulatory mechanism of gastric emptying in humans. We show that increasing interleukin (IL)-6 concentrations delays gastric emptying leading to reduced postprandial glycemia. IL-6 furthermore reduces insulin secretion in a GLP-1-dependent manner while effects on gastric emptying are GLP-1 independent...
April 28, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29754951/mitochondrial-translation-efficiency-controls-cytoplasmic-protein-homeostasis
#6
Tamara Suhm, Jayasankar Mohanakrishnan Kaimal, Hannah Dawitz, Carlotta Peselj, Anna E Masser, Sarah Hanzén, Matevž Ambrožič, Agata Smialowska, Markus L Björck, Peter Brzezinski, Thomas Nyström, Sabrina Büttner, Claes Andréasson, Martin Ott
Cellular proteostasis is maintained via the coordinated synthesis, maintenance, and breakdown of proteins in the cytosol and organelles. While biogenesis of the mitochondrial membrane complexes that execute oxidative phosphorylation depends on cytoplasmic translation, it is unknown how translation within mitochondria impacts cytoplasmic proteostasis and nuclear gene expression. Here we have analyzed the effects of mutations in the highly conserved accuracy center of the yeast mitoribosome. Decreased accuracy of mitochondrial translation shortened chronological lifespan, impaired management of cytosolic protein aggregates, and elicited a general transcriptional stress response...
April 24, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29706566/fgf21-prevents-angiotensin-ii-induced-hypertension-and-vascular-dysfunction-by-activation-of-ace2-angiotensin-1-7-axis-in-mice
#7
Xuebo Pan, Yihui Shao, Fan Wu, Yuan Wang, Rongrong Xiong, Jujia Zheng, Haishan Tian, Baile Wang, Yanfang Wang, Yi Zhang, Zongsheng Han, Aijuan Qu, Haixia Xu, Aihua Lu, Tianxin Yang, Xiaokun Li, Aimin Xu, Jie Du, Zhuofeng Lin
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage...
April 24, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29706567/dgat2-inhibition-alters-aspects-of-triglyceride-metabolism-in-rodents-but-not-in-non-human-primates
#8
David G McLaren, Seongah Han, Beth Ann Murphy, Larissa Wilsie, Steven J Stout, Haihong Zhou, Thomas P Roddy, Judith N Gorski, Daniel E Metzger, Myung K Shin, Dermot F Reilly, Heather H Zhou, Marija Tadin-Strapps, Steven R Bartz, Anne-Marie Cumiskey, Thomas H Graham, Dong-Ming Shen, Karen O Akinsanya, Stephen F Previs, Jason E Imbriglio, Shirly Pinto
Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low-density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhibitors and gene silencing both in vitro and in vivo. Consistent with prior reports, chronic inhibition of DGAT2 in a murine model of obesity led to correction of multiple lipid parameters...
April 20, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29685734/quantitative-analysis-of-nad-synthesis-breakdown-fluxes
#9
Ling Liu, Xiaoyang Su, William J Quinn, Sheng Hui, Kristin Krukenberg, David W Frederick, Philip Redpath, Le Zhan, Karthikeyani Chellappa, Eileen White, Marie Migaud, Timothy J Mitchison, Joseph A Baur, Joshua D Rabinowitz
The redox cofactor nicotinamide adenine dinucleotide (NAD) plays a central role in metabolism and is a substrate for signaling enzymes including poly-ADP-ribose-polymerases (PARPs) and sirtuins. NAD concentration falls during aging, which has triggered intense interest in strategies to boost NAD levels. A limitation in understanding NAD metabolism has been reliance on concentration measurements. Here, we present isotope-tracer methods for NAD flux quantitation. In cell lines, NAD was made from nicotinamide and consumed largely by PARPs and sirtuins...
April 20, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29706565/aldolase-b-mediated-fructose-metabolism-drives-metabolic-reprogramming-of-colon-cancer-liver-metastasis
#10
Pengcheng Bu, Kai-Yuan Chen, Kun Xiang, Christelle Johnson, Scott B Crown, Nikolai Rakhilin, Yiwei Ai, Lihua Wang, Rui Xi, Inna Astapova, Yan Han, Jiahe Li, Bradley B Barth, Min Lu, Ziyang Gao, Robert Mines, Liwen Zhang, Mark Herman, David Hsu, Guo-Fang Zhang, Xiling Shen
Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation...
April 18, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29681442/evidence-that-tlr4-is-not-a-receptor-for-saturated-fatty-acids-but-mediates-lipid-induced-inflammation-by-reprogramming-macrophage-metabolism
#11
Graeme I Lancaster, Katherine G Langley, Nils Anton Berglund, Helene L Kammoun, Saskia Reibe, Emma Estevez, Jacquelyn Weir, Natalie A Mellett, Gerard Pernes, James R W Conway, Man K S Lee, Paul Timpson, Andrew J Murphy, Seth L Masters, Steve Gerondakis, Nenad Bartonicek, Dominik C Kaczorowski, Marcel E Dinger, Peter J Meikle, Peter J Bond, Mark A Febbraio
Chronic inflammation is a hallmark of obesity and is linked to the development of numerous diseases. The activation of toll-like receptor 4 (TLR4) by long-chain saturated fatty acids (lcSFAs) is an important process in understanding how obesity initiates inflammation. While experimental evidence supports an important role for TLR4 in obesity-induced inflammation in vivo, via a mechanism thought to involve direct binding to and activation of TLR4 by lcSFAs, several lines of evidence argue against lcSFAs being direct TLR4 agonists...
April 13, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29657029/the-hormone-fgf21-stimulates-water-drinking-in-response-to-ketogenic-diet-and-alcohol
#12
Parkyong Song, Christoph Zechner, Genaro Hernandez, José Cánovas, Yang Xie, Varun Sondhi, Martin Wagner, Vanessa Stadlbauer, Angela Horvath, Bettina Leber, Ming Chang Hu, Orson W Moe, David J Mangelsdorf, Steven A Kliewer
Alcohol and ketogenic diets increase water consumption. Here, we show that the hormone FGF21 is required for this drinking response in mice. Circulating levels of FGF21 are increased by alcohol consumption in humans and by both alcohol and ketogenic diets in mice. Pharmacologic administration of FGF21 stimulates water drinking behavior in mice within 2 hr. Concordantly, mice lacking FGF21 fail to increase water intake in response to either alcohol or a ketogenic diet. The effect of FGF21 on drinking is mediated in part by SIM1-positive neurons of the hypothalamus and is inhibited by β-adrenergic receptor antagonists...
April 12, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29657030/rewiring-of-glutamine-metabolism-is-a-bioenergetic-adaptation-of-human-cells-with-mitochondrial-dna-mutations
#13
Qiuying Chen, Kathryne Kirk, Yevgeniya I Shurubor, Dazhi Zhao, Andrea J Arreguin, Ifrah Shahi, Federica Valsecchi, Guido Primiano, Elizabeth L Calder, Valerio Carelli, Travis T Denton, M Flint Beal, Steven S Gross, Giovanni Manfredi, Marilena D'Aurelio
Using molecular, biochemical, and untargeted stable isotope tracing approaches, we identify a previously unappreciated glutamine-derived α-ketoglutarate (αKG) energy-generating anaplerotic flux to be critical in mitochondrial DNA (mtDNA) mutant cells that harbor human disease-associated oxidative phosphorylation defects. Stimulating this flux with αKG supplementation enables the survival of diverse mtDNA mutant cells under otherwise lethal obligatory oxidative conditions. Strikingly, we demonstrate that when residual mitochondrial respiration in mtDNA mutant cells exceeds 45% of control levels, αKG oxidative flux prevails over reductive carboxylation...
April 9, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29657031/warming-induces-significant-reprogramming-of-beige-but-not-brown-adipocyte-cellular-identity
#14
Hyun Cheol Roh, Linus T Y Tsai, Mengle Shao, Danielle Tenen, Yachen Shen, Manju Kumari, Anna Lyubetskaya, Christopher Jacobs, Brian Dawes, Rana K Gupta, Evan D Rosen
Beige and brown adipocytes generate heat in response to reductions in ambient temperature. When warmed, both beige and brown adipocytes exhibit morphological "whitening," but it is unknown whether or to what extent this represents a true shift in cellular identity. Using cell-type-specific profiling in vivo, we uncover a unique paradigm of temperature-dependent epigenomic plasticity of beige, but not brown, adipocytes, with conversion from a brown to a white chromatin state. Despite this profound shift in cellular identity, warm whitened beige adipocytes retain an epigenomic memory of prior cold exposure defined by an array of poised enhancers that prime thermogenic genes for rapid response during a second bout of cold exposure...
April 5, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29606596/metabolic-maturation-during-muscle-stem-cell-differentiation-is-achieved-by-mir-1-133a-mediated-inhibition-of-the-dlk1-dio3-mega-gene-cluster
#15
Stas Wüst, Stefan Dröse, Juliana Heidler, Ilka Wittig, Ina Klockner, Andras Franko, Erik Bonke, Stefan Günther, Ulrich Gärtner, Thomas Boettger, Thomas Braun
Muscle stem cells undergo a dramatic metabolic switch to oxidative phosphorylation during differentiation, which is achieved by massively increased mitochondrial activity. Since expression of the muscle-specific miR-1/133a gene cluster correlates with increased mitochondrial activity during muscle stem cell (MuSC) differentiation, we examined the potential role of miR-1/133a in metabolic maturation of skeletal muscles in mice. We found that miR-1/133a downregulate Mef2A in differentiated myocytes, thereby suppressing the Dlk1-Dio3 gene cluster, which encodes multiple microRNAs inhibiting expression of mitochondrial genes...
March 28, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29628419/increased-tumor-glycolysis-characterizes-immune-resistance-to-adoptive-t-cell-therapy
#16
Tina Cascone, Jodi A McKenzie, Rina M Mbofung, Simone Punt, Zhe Wang, Chunyu Xu, Leila J Williams, Zhiqiang Wang, Christopher A Bristow, Alessandro Carugo, Michael D Peoples, Lerong Li, Tatiana Karpinets, Lu Huang, Shruti Malu, Caitlin Creasy, Sara E Leahey, Jiong Chen, Yuan Chen, Helen Pelicano, Chantale Bernatchez, Y N Vashisht Gopal, Timothy P Heffernan, Jianhua Hu, Jing Wang, Rodabe N Amaria, Levi A Garraway, Peng Huang, Peiying Yang, Ignacio I Wistuba, Scott E Woodman, Jason Roszik, R Eric Davis, Michael A Davies, John V Heymach, Patrick Hwu, Weiyi Peng
Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis-related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo...
March 17, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29606597/the-torc1-regulated-cpa-complex-rewires-an-rna-processing-network-to-drive-autophagy-and-metabolic-reprogramming
#17
Hong-Wen Tang, Yanhui Hu, Chiao-Lin Chen, Baolong Xia, Jonathan Zirin, Min Yuan, John M Asara, Leonard Rabinow, Norbert Perrimon
Nutrient deprivation induces autophagy through inhibiting TORC1 activity. We describe a novel mechanism in Drosophila by which TORC1 regulates RNA processing of Atg transcripts and alters ATG protein levels and activities via the cleavage and polyadenylation (CPA) complex. We show that TORC1 signaling inhibits CDK8 and DOA kinases, which directly phosphorylate CPSF6, a component of the CPA complex. These phosphorylation events regulate CPSF6 localization, RNA binding, and starvation-induced alternative RNA processing of transcripts involved in autophagy, nutrient, and energy metabolism, thereby controlling autophagosome formation and metabolism...
March 16, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29576535/metabolic-slowing-and-reduced-oxidative-damage-with-sustained-caloric-restriction-support-the-rate-of-living-and-oxidative-damage-theories-of-aging
#18
Leanne M Redman, Steven R Smith, Jeffrey H Burton, Corby K Martin, Dora Il'yasova, Eric Ravussin
Calorie restriction (CR) is a dietary intervention with potential benefits for healthspan improvement and lifespan extension. In 53 (34 CR and 19 control) non-obese adults, we tested the hypothesis that energy expenditure (EE) and its endocrine mediators are reduced with a CR diet over 2 years. Approximately 15% CR was achieved over 2 years, resulting in an average 8.7 kg weight loss, whereas controls gained 1.8 kg. In the CR group, EE measured over 24 hr or during sleep was approximately 80-120 kcal/day lower than expected on the basis of weight loss, indicating sustained metabolic adaptation over 2 years...
March 12, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29719235/glucose-homeostasis-is-important-for-immune-cell-viability-during-candida-challenge-and-host-survival-of-systemic-fungal-infection
#19
Timothy M Tucey, Jiyoti Verma, Paul F Harrison, Sarah L Snelgrove, Tricia L Lo, Allison K Scherer, Adele A Barugahare, David R Powell, Robert T Wheeler, Michael J Hickey, Traude H Beilharz, Thomas Naderer, Ana Traven
To fight infections, macrophages undergo a metabolic shift whereby increased glycolysis fuels antimicrobial inflammation and killing of pathogens. Here we demonstrate that the pathogen Candida albicans turns this metabolic reprogramming into an Achilles' heel for macrophages. During Candida-macrophage interactions intertwined metabolic shifts occur, with concomitant upregulation of glycolysis in both host and pathogen setting up glucose competition. Candida thrives on multiple carbon sources, but infected macrophages are metabolically trapped in glycolysis and depend on glucose for viability: Candida exploits this limitation by depleting glucose, triggering rapid macrophage death...
May 1, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29719234/maximizing-cellular-adaptation-to-endurance-exercise-in-skeletal-muscle
#20
REVIEW
John A Hawley, Carsten Lundby, James D Cotter, Louise M Burke
The application of molecular techniques to exercise biology has provided novel insight into the complexity and breadth of intracellular signaling networks involved in response to endurance-based exercise. Here we discuss several strategies that have high uptake by athletes and, on mechanistic grounds, have the potential to promote cellular adaptation to endurance training in skeletal muscle. Such approaches are based on the underlying premise that imposing a greater metabolic load and provoking extreme perturbations in cellular homeostasis will augment acute exercise responses that, when repeated over months and years, will amplify training adaptation...
May 1, 2018: Cell Metabolism
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