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781 results on '"Semenkovich, Clay F."'

1. Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress

Author

Korobkina, Ekaterina D., Calejman, Camila Martinez, Haley, John A., Kelly, Miranda E., Li, Huawei, Gaughan, Maria, Chen, Qingbo, Pepper, Hannah L., Ahmad, Hafsah, Boucher, Alexander, Fluharty, Shelagh M., Lin, Te-Yueh, Lotun, Anoushka, Peura, Jessica, Trefely, Sophie, Green, Courtney R., Vo, Paula, Semenkovich, Clay F., Pitarresi, Jason R., Spinelli, Jessica B., Aydemir, Ozkan, Metallo, Christian M., Lynes, Matthew D., Jang, Cholsoon, Snyder, Nathaniel W., Wellen, Kathryn E., and Guertin, David A.

Published
2024
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3. Fatty acid synthesis suppresses dietary polyunsaturated fatty acid use

Author

Worthmann, Anna, Ridder, Julius, Piel, Sharlaine Y. L., Evangelakos, Ioannis, Musfeldt, Melina, Voß, Hannah, O’Farrell, Marie, Fischer, Alexander W., Adak, Sangeeta, Sundd, Monica, Siffeti, Hasibullah, Haumann, Friederike, Kloth, Katja, Bierhals, Tatjana, Heine, Markus, Pertzborn, Paul, Pauly, Mira, Scholz, Julia-Josefine, Kundu, Suman, Fuh, Marceline M., Neu, Axel, Tödter, Klaus, Hempel, Maja, Knippschild, Uwe, Semenkovich, Clay F., Schlüter, Hartmut, Heeren, Joerg, Scheja, Ludger, Kubisch, Christian, and Schlein, Christian

Published
2024
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5. Suppressing fatty acid synthase by type I interferon and chemical inhibitors as a broad spectrum anti-viral strategy against SARS-CoV-2

Author

Aliyari, Saba R, Ghaffari, Amir Ali, Pernet, Olivier, Parvatiyar, Kislay, Wang, Yao, Gerami, Hoda, Tong, Ann-Jay, Vergnes, Laurent, Takallou, Armin, Zhang, Adel, Wei, Xiaochao, Chilin, Linda D, Wu, Yuntao, Semenkovich, Clay F, Reue, Karen, Smale, Stephen T, Lee, Benhur, and Cheng, Genhong

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Biodefense, Prevention, Pneumonia, Infectious Diseases, Pneumonia & Influenza, Vaccine Related, Lung, Emerging Infectious Diseases, 5.1 Pharmaceuticals, Aetiology, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Fatty acid synthase, FASN, IFN-I, SARS-CoV-2, COVID-19, C75, Cerulenin, TVB-3166, Pharmacology and pharmaceutical sciences
Abstract

SARS-CoV-2 is an emerging viral pathogen and a major global public health challenge since December of 2019, with limited effective treatments throughout the pandemic. As part of the innate immune response to viral infection, type I interferons (IFN-I) trigger a signaling cascade that culminates in the activation of hundreds of genes, known as interferon stimulated genes (ISGs), that collectively foster an antiviral state. We report here the identification of a group of type I interferon suppressed genes, including fatty acid synthase (FASN), which are involved in lipid metabolism. Overexpression of FASN or the addition of its downstream product, palmitate, increased viral infection while knockout or knockdown of FASN reduced infection. More importantly, pharmacological inhibitors of FASN effectively blocked infections with a broad range of viruses, including SARS-CoV-2 and its variants of concern. Thus, our studies not only suggest that downregulation of metabolic genes may present an antiviral strategy by type I interferon, but they also introduce the potential for FASN inhibitors to have a therapeutic application in combating emerging infectious diseases such as COVID-19.

Published
2022

14. Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration

Author

Spears, Larry D., Adak, Sangeeta, Dong, Guifang, Wei, Xiaochao, Spyropoulos, George, Zhang, Qiang, Yin, Li, Feng, Chu, Hu, Donghua, Lodhi, Irfan J., Hsu, Fong-Fu, Rajagopal, Rithwick, Noguchi, Kevin K., Halabi, Carmen M., Brier, Lindsey, Bice, Annie R., Lananna, Brian V., Musiek, Erik S., Avraham, Oshri, Cavalli, Valeria, Holth, Jerrah K., Holtzman, David M., Wozniak, David F., Culver, Joseph P., and Semenkovich, Clay F.

Published
2021
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15. FASN-Dependent Lipid Metabolism Links Neurogenic Stem/Progenitor Cell Activity to Learning and Memory Deficits

Author

Bowers, Megan, Liang, Tong, Gonzalez-Bohorquez, Daniel, Zocher, Sara, Jaeger, Baptiste N., Kovacs, Werner J., Röhrl, Clemens, Cramb, Kaitlyn M.L., Winterer, Jochen, Kruse, Merit, Dimitrieva, Slavica, Overall, Rupert W., Wegleiter, Thomas, Najmabadi, Hossein, Semenkovich, Clay F., Kempermann, Gerd, Földy, Csaba, and Jessberger, Sebastian

Published
2020
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18. Insulin regulates lymphatic endothelial function via palmitoylation

Author

Gonzalez-Nieves, Silvia, primary, Wei, Xiaochao, additional, McQuillan, Jay, additional, Zhang, Qiang, additional, Zhang, Jinsong, additional, McGuffee, Reagan M, additional, Ford, David A, additional, Love-Gregory, Latisha, additional, Abumrad, Nada A, additional, Gelman, Andrew E, additional, Semenkovich, Clay F, additional, and Cifarelli, Vincenza, additional

Published
2024
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19. Effects of microbiota-directed foods in gnotobiotic animals and undernourished children

Author

Gehrig, Jeanette L., Venkatesh, Siddarth, Chang, Hao-Wei, Hibberd, Matthew C., Kung, Vanderlene L., Cheng, Jiye, Chen, Robert Y., Subramanian, Sathish, Cowardin, Carrie A., Meier, Martin F., O’Donnell, David, Talcott, Michael, Spears, Larry D., Semenkovich, Clay F., Henrissat, Bernard, Giannone, Richard J., Hettich, Robert L., Ilkayeva, Olga, Muehlbauer, Michael, Newgard, Christopher B., Sawyer, Christopher, Head, Richard D., Rodionov, Dmitry A., Arzamasov, Aleksandr A., Leyn, Semen A., Osterman, Andrei L., Hossain, Md Iqbal, Islam, Munirul, Choudhury, Nuzhat, Sarker, Shafiqul Alam, Huq, Sayeeda, Mahmud, Imteaz, Mostafa, Ishita, Mahfuz, Mustafa, Barratt, Michael J., Ahmed, Tahmeed, and Gordon, Jeffrey I.

Published
2019

20. Inactivation of fatty acid synthase impairs hepatocarcinogenesis driven by AKT in mice and humans

Author

Li, Lei, Pilo, Giulia M, Li, Xiaolei, Cigliano, Antonio, Latte, Gavinella, Che, Li, Joseph, Christy, Mela, Marta, Wang, Chunmei, Jiang, Lijie, Ribback, Silvia, Simile, Maria M, Pascale, Rosa M, Dombrowski, Frank, Evert, Matthias, Semenkovich, Clay F, Chen, Xin, and Calvisi, Diego F

Subjects
Medical Biotechnology, Biomedical and Clinical Sciences, Chronic Liver Disease and Cirrhosis, Genetics, Cancer, Liver Cancer, Rare Diseases, Liver Disease, Digestive Diseases, Animals, Apoptosis, Carcinogenesis, Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Proliferation, Fatty Acid Synthase, Type I, Gene Expression Regulation, Neoplastic, Humans, Liver, Liver Neoplasms, Mice, Phosphorylation, Proto-Oncogene Proteins c-akt, Signal Transduction, Hepatocellular carcinoma, Lipogenesis, Fatty acid synthase, AKT, Rictor, Clinical Sciences, Public Health and Health Services, Gastroenterology & Hepatology, Clinical sciences
Abstract

Background & aimsCumulating evidence underlines the crucial role of aberrant lipogenesis in human hepatocellular carcinoma (HCC). Here, we investigated the oncogenic potential of fatty acid synthase (FASN), the master regulator of de novo lipogenesis, in the mouse liver.MethodsFASN was overexpressed in the mouse liver, either alone or in combination with activated N-Ras, c-Met, or SCD1, via hydrodynamic injection. Activated AKT was overexpressed via hydrodynamic injection in livers of conditional FASN or Rictor knockout mice. FASN was suppressed in human hepatoma cell lines via specific small interfering RNA.ResultsOverexpression of FASN, either alone or in combination with other genes associated with hepatocarcinogenesis, did not induce histological liver alterations. In contrast, genetic ablation of FASN resulted in the complete inhibition of hepatocarcinogenesis in AKT-overexpressing mice. In human HCC cell lines, FASN inactivation led to a decline in cell proliferation and a rise in apoptosis, which were paralleled by a decrease in the levels of phosphorylated/activated AKT, an event controlled by the mammalian target of rapamycin complex 2 (mTORC2). Downregulation of AKT phosphorylation/activation following FASN inactivation was associated with a strong inhibition of rapamycin-insensitive companion of mTOR (Rictor), the major component of mTORC2, at post-transcriptional level. Finally, genetic ablation of Rictor impaired AKT-driven hepatocarcinogenesis in mice.ConclusionsFASN is not oncogenic per se in the mouse liver, but is necessary for AKT-driven hepatocarcinogenesis. Pharmacological blockade of FASN might be highly useful in the treatment of human HCC characterized by activation of the AKT pathway.

Published
2016

22. Functional and epigenetic phenotypes of humans and mice with DNMT3A Overgrowth Syndrome

Author

Smith, Amanda M., LaValle, Taylor A., Shinawi, Marwan, Ramakrishnan, Sai M., Abel, Haley J., Hill, Cheryl A., Kirkland, Nicole M., Rettig, Michael P., Helton, Nichole M., Heath, Sharon E., Ferraro, Francesca, Chen, David Y., Adak, Sangeeta, Semenkovich, Clay F., Christian, Diana L., Martin, Jenna R., Gabel, Harrison W., Miller, Christopher A., and Ley, Timothy J.

Published
2021
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23. Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

Author

Bruning, Ulrike, Morales-Rodriguez, Francisco, Kalucka, Joanna, Goveia, Jermaine, Taverna, Federico, Queiroz, Karla C.S., Dubois, Charlotte, Cantelmo, Anna Rita, Chen, Rongyuan, Loroch, Stefan, Timmerman, Evy, Caixeta, Vanessa, Bloch, Katarzyna, Conradi, Lena-Christin, Treps, Lucas, Staes, An, Gevaert, Kris, Tee, Andrew, Dewerchin, Mieke, Semenkovich, Clay F., Impens, Francis, Schilling, Birgit, Verdin, Eric, Swinnen, Johannes V., Meier, Jordan L., Kulkarni, Rhushikesh A., Sickmann, Albert, Ghesquière, Bart, Schoonjans, Luc, Li, Xuri, Mazzone, Massimiliano, and Carmeliet, Peter

Published
2018
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25. Gut Microbiota from Twins Discordant for Obesity Modulate Metabolism in Mice

Author

Ridaura, Vanessa K, Faith, Jeremiah J, Rey, Federico E, Cheng, Jiye, Duncan, Alexis E, Kau, Andrew L, Griffin, Nicholas W, Lombard, Vincent, Henrissat, Bernard, Bain, James R, Muehlbauer, Michael J, Ilkayeva, Olga, Semenkovich, Clay F, Funai, Katsuhiko, Hayashi, David K, Lyle, Barbara J, Martini, Margaret C, Ursell, Luke K, Clemente, Jose C, Van Treuren, William, Walters, William A, Knight, Rob, Newgard, Christopher B, Heath, Andrew C, and Gordon, Jeffrey I

Subjects
Prevention, Obesity, Nutrition, Aetiology, 2.1 Biological and endogenous factors, Cardiovascular, Oral and gastrointestinal, Stroke, Metabolic and endocrine, Adiposity, Adult, Animals, Bacteroidetes, Cecum, Diet, Fat-Restricted, Feces, Female, Gastrointestinal Tract, Germ-Free Life, Humans, Metabolome, Metagenome, Mice, Mice, Inbred C57BL, Mice, Obese, Thinness, Twins, Weight Gain, Young Adult, General Science & Technology
Abstract

The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the U.S. diet. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes, were transmissible with uncultured fecal communities and with their corresponding fecal bacterial culture collections. Cohousing mice harboring an obese twin's microbiota (Ob) with mice containing the lean co-twin's microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cage mates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota and was diet-dependent. These findings reveal transmissible, rapid, and modifiable effects of diet-by-microbiota interactions.

Published
2013

26. The Mitochondrial Proteins NLRX1 and TUFM Form a Complex that Regulates Type I Interferon and Autophagy

Author

Lei, Yu, Wen, Haitao, Yu, Yanbao, Taxman, Debra J, Zhang, Lu, Widman, Douglas G, Swanson, Karen V, Wen, Kwun-Wah, Damania, Blossom, Moore, Chris B, Giguère, Patrick M, Siderovski, David P, Hiscott, John, Razani, Babak, Semenkovich, Clay F, Chen, Xian, and Ting, Jenny P-Y

Subjects
Biomedical and Clinical Sciences, Immunology, Underpinning research, 1.1 Normal biological development and functioning, Infection, Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Animals, Autophagy, Autophagy-Related Protein 12, Autophagy-Related Protein 5, Autophagy-Related Proteins, Carrier Proteins, Cytokines, DEAD Box Protein 58, DEAD-box RNA Helicases, Fibroblasts, Gene Expression Regulation, HEK293 Cells, Humans, Interferon Type I, Macrophages, Peritoneal, Mice, Microtubule-Associated Proteins, Mitochondrial Proteins, Molecular Sequence Data, Multiprotein Complexes, Peptide Elongation Factor Tu, Protein Interaction Mapping, Proteins, Recombinant Fusion Proteins, Sequence Alignment, Sequence Homology, Amino Acid, Specific Pathogen-Free Organisms, Vesiculovirus
Abstract

The mitochondrial protein MAVS (also known as IPS-1, VISA, and CARDIF) interacts with RIG-I-like receptors (RLRs) to induce type I interferon (IFN-I). NLRX1 is a mitochondrial nucleotide-binding, leucine-rich repeats (NLR)-containing protein that attenuates MAVS-RLR signaling. Using Nlrx1(-/-) cells, we confirmed that NLRX1 attenuated IFN-I production, but additionally promoted autophagy during viral infection. This dual function of NLRX1 paralleled the previously described functions of the autophagy-related proteins Atg5-Atg12, but NLRX1 did not associate with Atg5-Atg12. High-throughput quantitative mass spectrometry and endogenous protein-protein interaction revealed an NLRX1-interacting partner, mitochondrial Tu translation elongation factor (TUFM). TUFM interacted with Atg5-Atg12 and Atg16L1 and has similar functions as NLRX1 by inhibiting RLR-induced IFN-I but promoting autophagy. In the absence of NLRX1, increased IFN-I and decreased autophagy provide an advantage for host defense against vesicular stomatitis virus. This study establishes a link between an NLR protein and the viral-induced autophagic machinery via an intermediary partner, TUFM.

Published
2012

31. Depalmitoylation and cell physiology: APT1 as a mediator of metabolic signals.

Author

Speck, Sarah L., Wei, Xiaochao, and Semenkovich, Clay F.

Subjects
CELL physiology, METABOLIC disorders, DISEASE complications, HOMEOSTASIS, ISLANDS of Langerhans, POST-translational modification, WESTERN countries
Abstract

More than half of the global population is obese or overweight, especially in Western countries, and this excess adiposity disrupts normal physiology to cause chronic diseases. Diabetes, an adiposity-associated epidemic disease, affects >500 million people, and cases are projected to exceed 1 billion before 2050. Lipid excess can impact physiology through the posttranslational modification of proteins, including the reversible process of S-palmitoylation. Dynamic palmitoylation cycling requires the S-acylation of proteins by acyltransferases and the depalmitoylation of these proteins mediated in part by acyl-protein thioesterases (APTs) such as APT1. Emerging evidence points to tissue-specific roles for the depalmitoylase APT1 in maintaining homeostasis in the vasculature, pancreatic islets, and liver. These recent findings raise the possibility that APT1 substrates can be therapeutically targeted to treat the complications of metabolic diseases. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Legionella pneumophila usurps host cell lipids for vacuole expansion and bacterial growth.

Author

Ghosh, Soma, Bandyopadhyay, Saumya, Smith, Danielle M., Adak, Sangeeta, Semenkovich, Clay F., Nagy, Laszlo, Wolfgang, Michael J., and O'Connor, Tamara J.

Subjects
LEGIONELLA pneumophila, BACTERIAL growth, FATTY acids, LEGIONELLA, LIPIDS, IMMUNE system, CELL compartmentation
Abstract

Vacuolar pathogens reside in membrane-bound compartments within host cells. Maintaining the integrity of this compartment is paramount to bacterial survival and replication as it protects against certain host surveillance mechanisms that function to eradicate invading pathogens. Preserving this compartment during bacterial replication requires expansion of the vacuole membrane to accommodate the increasing number of bacteria, and yet, how this is accomplished remains largely unknown. Here, we show that the vacuolar pathogen Legionella pneumophila exploits multiple sources of host cell fatty acids, including inducing host cell fatty acid scavenging pathways, in order to promote expansion of the replication vacuole and bacteria growth. Conversely, when exogenous lipids are limited, the decrease in host lipid availability restricts expansion of the replication vacuole membrane, resulting in a higher density of bacteria within the vacuole. Modifying the architecture of the vacuole prioritizes bacterial growth by allowing the greatest number of bacteria to remain protected by the vacuole membrane despite limited resources for its expansion. However, this trade-off is not without risk, as it can lead to vacuole destabilization, which is detrimental to the pathogen. However, when host lipid resources become extremely scarce, for example by inhibiting host lipid scavenging, de novo biosynthetic pathways, and/or diverting host fatty acids to storage compartments, bacterial replication becomes severely impaired, indicating that host cell fatty acid availability also directly regulates L. pneumophila growth. Collectively, these data demonstrate dual roles for host cell fatty acids in replication vacuole expansion and bacterial proliferation, revealing the central functions for these molecules and their metabolic pathways in L. pneumophila pathogenesis. Author summary: The pathogenesis of bacteria depends on their ability to avoid detection and killing by the host immune system while simultaneously competing with the host for nutrients. Here, we demonstrate that host cell fatty acids are paramount to the intracellular survival and replication of the bacterial pathogen Legionella. Legionella infection induces host cell fatty acid scavenging allowing for critical expansion of its replication vacuole, which protects against recognition by host surveillance pathways, and mediates robust bacterial proliferation. However, if host cell fatty acid availability becomes limited, vacuole membrane expansion is constrained, often leading to vacuole destabilization, and bacterial growth is restricted. Our findings reveal a central role for host cell fatty acids and their metabolic pathways in bacterial pathogenesis, whereby both the host and the pathogen define a gradient of available host fatty acids that can be manipulated by either organism to their benefit. [ABSTRACT FROM AUTHOR]

Published
2024
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42. A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome

Author

Lu, Simin, Kanekura, Kohsuke, Hara, Takashi, Mahadevan, Jana, Spears, Larry D., Oslowski, Christine M., Martinez, Rita, Yamazaki-Inoue, Mayu, Toyoda, Masashi, Neilson, Amber, Blanner, Patrick, Brown, Cris M., Semenkovich, Clay F., Marshall, Bess A., Hershey, Tamara, Umezawa, Akihiro, Greer, Peter A., and Urano, Fumihiko

Published
2014

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