25 results on '"Nada Y. Kalaany"'
Search Results
2. Starved epithelial cells uptake extracellular matrix for survival
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Taru Muranen, Marcin P. Iwanicki, Natasha L. Curry, Julie Hwang, Cory D. DuBois, Jonathan L. Coloff, Daniel S. Hitchcock, Clary B. Clish, Joan S. Brugge, and Nada Y. Kalaany
- Subjects
Science - Abstract
Inhibition of PI3K/mTOR, which mimics nutrient starvation, causes death of detached but not matrix-attached cancer cells. Here the authors show that nutrient restriction of epithelial cells causes uptake of the matrix protein laminin, which results in increased intracellular amino acids and enhanced mTORC1 signalling.
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- 2017
- Full Text
- View/download PDF
3. Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer
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Min-Sik Lee, Courtney Dennis, Insia Naqvi, Lucas Dailey, Alireza Lorzadeh, George Ye, Tamara Zaytouni, Ashley Adler, Daniel S. Hitchcock, Lin Lin, Megan T. Hoffman, Aladdin M. Bhuiyan, Jaimie L. Barth, Miranda E. Machacek, Mari Mino-Kenudson, Stephanie K. Dougan, Unmesh Jadhav, Clary B. Clish, and Nada Y. Kalaany
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Multidisciplinary - Published
- 2023
4. Supplementary Video 1 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
- Abstract
MOV file - 7511KB, Acute autophagy ablation causes progressive motor and behavioral deficits.
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- 2023
5. Supplementary Table 4 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
- Abstract
PDF file - 2587KB, Comparison of collapsed expression of all muscle genes during fasting.
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- 2023
6. Supplementary Table 1 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
- Abstract
PDF file - 145KB, Differential expression analysis for significant biological processes by GO term DAVID Analysis for liver tissues during fasting.
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- 2023
7. Supplementary Table 2 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
- Abstract
PDF file - 116KB, Differential expression analysis for significant biological processes by GO term DAVID Analysis for muscle tissues during fasting.
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- 2023
8. Supplementary Data from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
- Abstract
PDF file - 3190KB, Supplementary Figures (S1-S6) provide additional characterization about effects of systemic autophagy ablation in normal adult tissues and tumors. Supplementary Methods supply detailed information of experiments.
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- 2023
9. Supplementary Table 3 from Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance
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Eileen White, Joshua D. Rabinowitz, Chang S. Chan, Tyler Jacks, Nada Y. Kalaany, Sinan Khor, Saurabh V Laddha, Xin Teng, Sandy Price, Jessie Yanxiang Guo, and Gizem Karsli-Uzunbas
- Abstract
PDF file - 2193KB, Comparison of collapsed expression of all liver genes during fasting.
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- 2023
10. Adaptation of pancreatic cancer cells to nutrient deprivation is reversible and requires glutamine synthetase stabilization by mTORC1
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Shariq Madha, Caroline A. Lewis, Peter DelNero, Pei-Yun Tsai, Min-Sik Lee, Frederick R. Roberts, Ramesh A. Shivdasani, Clary B. Clish, Insia Naqvi, Kim C. Honselmann, Sergey Naumenko, Meeta Mistry, Mari Mino-Kenudson, Ashley Adler, Nada Y. Kalaany, Thomas Hank, Unmesh Jadhav, Vicente Morales Oyarvide, and Daniel S. Hitchcock
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Multidisciplinary ,mTORC1 ,Metabolism ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,medicine.disease ,Phenotype ,Neoplasm Proteins ,Chromatin ,Cell biology ,Pancreatic Neoplasms ,Glutamine ,Glutamate-Ammonia Ligase ,Cell Line, Tumor ,Pancreatic cancer ,Glutamine synthetase ,Cancer cell ,Enzyme Stability ,Commentary ,medicine ,Humans ,Gene silencing ,Epigenetics ,Carcinoma, Pancreatic Ductal - Abstract
Pancreatic ductal adenocarcinoma (PDA) is a lethal, therapy-resistant cancer that thrives in a highly desmoplastic, nutrient-deprived microenvironment. Several studies investigated the effects of depriving PDA of either glucose or glutamine alone. However, the consequences on PDA growth and metabolism of limiting both preferred nutrients have remained largely unknown. Here, we report the selection for clonal human PDA cells that survive and adapt to limiting levels of both glucose and glutamine. We find that adapted clones exhibit increased growth in vitro and enhanced tumor-forming capacity in vivo. Mechanistically, adapted clones share common transcriptional and metabolic programs, including amino acid use for de novo glutamine and nucleotide synthesis. They also display enhanced mTORC1 activity that prevents the proteasomal degradation of glutamine synthetase (GS), the rate-limiting enzyme for glutamine synthesis. This phenotype is notably reversible, with PDA cells acquiring alterations in open chromatin upon adaptation. Silencing of GS suppresses the enhanced growth of adapted cells and mitigates tumor growth. These findings identify non-genetic adaptations to nutrient deprivation in PDA and highlight GS as a dependency that could be targeted therapeutically in pancreatic cancer patients.SignificancePancreatic ductal adenocarcinoma (PDA) is a highly lethal malignancy with no effective therapies. PDA aggressiveness partly stems from its ability to grow within a uniquely dense stroma restricting nutrient access. This study demonstrates that PDA clones that survive chronic nutrient deprivation acquire reversible non-genetic adaptations allowing them to switch between metabolic states optimal for growth under nutrient-replete or nutrient-deprived conditions. One contributing factor to this adaptation mTORC1 activation, which stabilizes glutamine synthetase (GS) necessary for glutamine generation in nutrient-deprived cancer cells. Our findings imply that although total GS levels may not be a prognostic marker for aggressive disease, GS inhibition is of high therapeutic value, as it targets specific cell clusters adapted to nutrient starvation, thus mitigating tumor growth.
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- 2021
11. Abstract PO-029: Pancreatic cancer-associated cachexia as a 3-stage systemic disease with changes in body composition, tissue-specific wasting across time and alterations in glucose metabolism
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Blanca Majem, Insia Naqvi, Courtney Dennis, Nada Y. Kalaany, Clary B. Clish, and Lucas Dailey
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Cancer Research ,medicine.medical_specialty ,Systemic disease ,business.industry ,Carbohydrate metabolism ,medicine.disease ,Cachexia ,Endocrinology ,Oncology ,Internal medicine ,Pancreatic cancer ,medicine ,Tissue specific ,medicine.symptom ,Stage (cooking) ,business ,Wasting - Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease that rapidly deteriorates the organism resulting in 10% of body weight loss, together with specific changes in body composition in each stage, food intake only happening at the very end stage, while all non-tumoral tissues present significant reduced weight at early stages. We have performed metabolomics and lipidomics in all peripheral tissues, aiming to identify changes that occur not only at early- but also at the pre-CAC stages, when pancreatic tumors already weighed more than double of the normal pancreas. In addition, glucose tolerance test analyses showed that tumor-bearing mice cleared the glucose more rapidly than control mice, even at pre-CAC stages, opening new avenues to continue studying glucose metabolism in the periphery such as increased liver gluconeogenesis and peripheral insulin resistance. Together, these results allowed us to establish a murine model to study cachexia in 3 stages, similar to what happens in humans. Furthermore, metabolomic data from the peripheral tissues, tumor interstitial fluid (TIF) and plasma, will allow us to identify the metabolic landscape of the entire organism throughout the progression of the disease, and potentially propose new therapeutic windows to target or prevent wasting in cancer. Citation Format: Blanca Majem, Insia Naqvi, Courtney Dennis, Lucas Dailey, Clary B. Clish, Nada Kalaany. Pancreatic cancer-associated cachexia as a 3-stage systemic disease with changes in body composition, tissue-specific wasting across time and alterations in glucose metabolism [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-029.
- Published
- 2021
12. Critical role for arginase 2 in obesity-associated pancreatic cancer
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Lin Lin, Tamara Zaytouni, Patrick J Lenehan, Eduardo M. Torres, Daniel S. Hitchcock, Mari Mino-Kenudson, Nada Y. Kalaany, Cory D. Dubois, Vicente Morales-Oyarvide, Nicholas Stylopoulos, Elizaveta Freinkman, Brian M. Wolpin, Pei-Yun Tsai, and Clary B. Clish
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0301 basic medicine ,Male ,Ornithine ,medicine.medical_specialty ,congenital, hereditary, and neonatal diseases and abnormalities ,Arginine ,health care facilities, manpower, and services ,Science ,education ,General Physics and Astronomy ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Mucoproteins ,Internal medicine ,Pancreatic cancer ,health services administration ,medicine ,Animals ,Humans ,Obesity ,ARG1 ,ARG2 ,2. Zero hunger ,Mice, Knockout ,Oncogene Proteins ,Multidisciplinary ,Proteins ,General Chemistry ,Metabolism ,medicine.disease ,3. Good health ,Mitochondria ,Arginase ,Gene Expression Regulation, Neoplastic ,Pancreatic Neoplasms ,030104 developmental biology ,Endocrinology ,chemistry ,Urea cycle ,Carcinoma, Pancreatic Ductal - Abstract
Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDA remain unknown. Here we show that obesity-driven PDA exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDA. In vivo infusion of 15N-glutamine in obese mouse models of PDA demonstrates enhanced nitrogen flux into the urea cycle and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDA patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDA on ARG2 rather than the principal hepatic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer., Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDA). Here the authors show that obesity induces the expression of the mitochondrial form of arginase ARG2 in PDA and that ARG2 silencing or loss results in ammonia accumulation and suppression of obesity-driven PDA tumor growth.
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- 2017
13. Starved epithelial cells uptake extracellular matrix for survival
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Julie Hwang, Jonathan L. Coloff, Nada Y. Kalaany, Clary B. Clish, Natasha L. Curry, Joan S. Brugge, Taru A. Muranen, Marcin P. Iwanicki, Cory D. Dubois, and Daniel S. Hitchcock
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0301 basic medicine ,Programmed cell death ,Cell Survival ,medicine.medical_treatment ,Science ,General Physics and Astronomy ,Physiology ,Mice, Inbred Strains ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Extracellular matrix ,Phosphatidylinositol 3-Kinases ,03 medical and health sciences ,Laminin ,medicine ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,2. Zero hunger ,Multidisciplinary ,biology ,Chemistry ,Growth factor ,Integrin beta4 ,Epithelial Cells ,General Chemistry ,Fibroblasts ,Extracellular Matrix ,Cell biology ,030104 developmental biology ,Adipose Tissue ,Starvation ,Cell culture ,Cancer cell ,biology.protein ,Female - Abstract
Extracellular matrix adhesion is required for normal epithelial cell survival, nutrient uptake and metabolism. This requirement can be overcome by oncogene activation. Interestingly, inhibition of PI3K/mTOR leads to apoptosis of matrix-detached, but not matrix-attached cancer cells, suggesting that matrix-attached cells use alternate mechanisms to maintain nutrient supplies. Here we demonstrate that under conditions of dietary restriction or growth factor starvation, where PI3K/mTOR signalling is decreased, matrix-attached human mammary epithelial cells upregulate and internalize β4-integrin along with its matrix substrate, laminin. Endocytosed laminin localizes to lysosomes, results in increased intracellular levels of essential amino acids and enhanced mTORC1 signalling, preventing cell death. Moreover, we show that starved human fibroblasts secrete matrix proteins that maintain the growth of starved mammary epithelial cells contingent upon epithelial cell β4-integrin expression. Our study identifies a crosstalk between stromal fibroblasts and epithelial cells under starvation that could be exploited therapeutically to target tumours resistant to PI3K/mTOR inhibition., Inhibition of PI3K/mTOR, which mimics nutrient starvation, causes death of detached but not matrix-attached cancer cells. Here the authors show that nutrient restriction of epithelial cells causes uptake of the matrix protein laminin, which results in increased intracellular amino acids and enhanced mTORC1 signalling.
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- 2017
14. Author Correction: Tumours with PI3K activation are resistant to dietary restriction
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David M. Sabatini and Nada Y. Kalaany
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Oncology ,medicine.medical_specialty ,Multidisciplinary ,business.industry ,Internal medicine ,Published Erratum ,medicine ,MEDLINE ,business - Published
- 2020
15. Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis
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Elizaveta Freinkman, Yaotang Wu, Roderick T. Bronson, Natasha L. Curry, Min-Sik Lee, Nada Y. Kalaany, Michael Marcotrigiano, Morris F. White, Clary B. Clish, He Xu, Saketh Challa, Ashley Adler, Pei-Yun Tsai, Daniel S. Hitchcock, and Kyle D. Copps
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0301 basic medicine ,Lung Neoplasms ,Carcinogenesis ,Tumor initiation ,medicine.disease_cause ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Mice ,Carcinoma, Non-Small-Cell Lung ,medicine ,Autophagy ,Animals ,Humans ,Insulin ,Amino Acids ,Insulin-Like Growth Factor I ,neoplasms ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Insulin-like growth factor 1 receptor ,Multidisciplinary ,biology ,Chemistry ,Biological Sciences ,IRS2 ,IRS1 ,respiratory tract diseases ,Neoplasm Proteins ,Insulin receptor ,030104 developmental biology ,Genes, ras ,A549 Cells ,Proteolysis ,Cancer research ,biology.protein ,Codon, Terminator ,Insulin Receptor Substrate Proteins ,KRAS ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Non–small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (Irs1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with Irs1/Irs2 loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for KRAS-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in KRAS-mutant NSCLC.
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- 2018
16. Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction
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Tyler Jacks, Natasha L. Curry, Trudy G. Oliver, Nada Y. Kalaany, Mari Mino-Kenudson, Ömer H. Yilmaz, Jade Y. Moon, Vedat O. Yilmaz, David M. Sabatini, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Yilmaz, Omer, Jacks, Tyler E., Sabatini, David M., and Oliver, Trudy
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Lung Neoplasms ,Biology ,Article ,Proto-Oncogene Proteins p21(ras) ,Mice ,Phosphatidylinositol 3-Kinases ,Growth factor receptor ,Carcinoma, Non-Small-Cell Lung ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,PTEN ,Pyrophosphatases ,Lung cancer ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Caloric Restriction ,Insulin-like growth factor 1 receptor ,Oncogene Proteins ,Endoplasmic reticulum ,PTEN Phosphohydrolase ,Cancer ,respiratory system ,medicine.disease ,Disease Models, Animal ,Phenotype ,Oncology ,Cancer research ,biology.protein ,Proto-Oncogene Proteins c-akt - Abstract
PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction–resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction–sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non–small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss. SIGNIFICANCE: Our studies point to a heterogeneity of AKT activation in the same murine Pten-null lung tissue and in human NSCLC, further underscoring the challenges of personalizing cancer therapy based solely on cancer genotype. Our findings therefore indicate that the tumor response to anticancer therapies, including dietary restriction, needs to be based on PI3K/AKT activity per se, rather than on genetic alterations in the PTEN/PI3K pathway., Howard Hughes Medical Institute (Investigator), National Institutes of Health (U.S.) (NIH grant R01 AI047389), National Institutes of Health (U.S.) (NIH grant R01 CA129105), National Institutes of Health (U.S.) (NIH grant 2-P30-CA14051), Alexander and Margaret Stewart Trust (Award), Boston Children's Hospital, David H. Koch Institute for Integrative Cancer Research at MIT (Anna Fuller Fund fellowship)
- Published
- 2013
17. Abstract SY29-01: Role of nitrogen metabolism in obesity-associated pancreatic cancer
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Nada Y. Kalaany
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Cancer Research ,endocrine system diseases ,Arginine ,business.industry ,Cancer ,Ornithine ,medicine.disease ,Arginase ,chemistry.chemical_compound ,Oncology ,chemistry ,Pancreatic cancer ,Urea cycle ,medicine ,Cancer research ,business ,ARG1 ,ARG2 - Abstract
Obesity is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Despite recent identification of metabolic alterations in this lethal malignancy, the metabolic dependencies of obesity-associated PDAC remain unknown. Here we show that obesity-driven PDAC exhibits accelerated growth and a striking transcriptional enrichment for pathways regulating nitrogen metabolism. We find that the mitochondrial form of arginase (ARG2), which hydrolyzes arginine into ornithine and urea, is induced upon obesity, and silencing or loss of ARG2 markedly suppresses PDAC. In vivo infusion of 15N-glutamine in obese mouse models of PDAC demonstrates enhanced nitrogen flux into the urea cycle, and infusion of 15N-arginine shows that Arg2 loss causes significant ammonia accumulation that results from the shunting of arginine catabolism into alternative nitrogen repositories. Furthermore, analysis of PDAC patient tumors indicates that ARG2 levels correlate with body mass index (BMI). The specific dependency of PDAC on ARG2 rather than the principal hepatic ureagenic enzyme ARG1 opens a therapeutic window for obesity-associated pancreatic cancer. Citation Format: Nada Y. Kalaany. Role of nitrogen metabolism in obesity-associated pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY29-01.
- Published
- 2018
18. Ablation in Mice of the mTORC Components raptor, rictor, or mLST8 Reveals that mTORC2 Is Required for Signaling to Akt-FOXO and PKCα, but Not S6K1
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David A. Guertin, Nada Y. Kalaany, Carson C. Thoreen, Jason Moffat, Michael S. Brown, Deanna Stevens, Aurora A. Burds, Kevin Fitzgerald, and David M. Sabatini
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DEVBIO ,mTORC1 ,mTORC2 ,Fetal Development ,Glycogen Synthase Kinase 3 ,Mice ,0302 clinical medicine ,Insulin ,TOR complex ,Phosphorylation ,Cytoskeleton ,Mice, Knockout ,0303 health sciences ,TOR Serine-Threonine Kinases ,Forkhead Box Protein O3 ,digestive, oral, and skin physiology ,Forkhead Transcription Factors ,SIGNALING ,030220 oncology & carcinogenesis ,Gene Targeting ,FOXO3 ,biological phenomena, cell phenomena, and immunity ,Signal transduction ,Protein Binding ,Signal Transduction ,Protein Kinase C-alpha ,P70-S6 Kinase 1 ,Mechanistic Target of Rapamycin Complex 1 ,Biology ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Tuberous Sclerosis Complex 2 Protein ,Animals ,Fetal Viability ,Molecular Biology ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Glycogen Synthase Kinase 3 beta ,Ribosomal Protein S6 Kinases ,Tumor Suppressor Proteins ,Proteins ,Cell Biology ,Embryo, Mammalian ,Multiprotein Complexes ,Trans-Activators ,Cancer research ,Proto-Oncogene Proteins c-akt ,Transcription Factors ,Developmental Biology - Abstract
The mTOR kinase controls cell growth, proliferation, and survival through two distinct multiprotein complexes, mTORC1 and mTORC2. mTOR and mLST8 are in both complexes, while raptor and rictor are part of only mTORC1 and mTORC2, respectively. To investigate mTORC1 and mTORC2 function in vivo, we generated mice deficient for raptor, rictor, or mLST8. Like mice null for mTOR, those lacking raptor die early in development. However, mLST8 null embryos survive until e10.5 and resemble embryos missing rictor. mLST8 is necessary to maintain the rictor-mTOR, but not the raptor-mTOR, interaction, and both mLST8 and rictor are required for the hydrophobic motif phosphorylation of Akt/PKB and PKCalpha, but not S6K1. Furthermore, insulin signaling to FOXO3, but not to TSC2 or GSK3beta, requires mLST8 and rictor. Thus, mTORC1 function is essential in early development, mLST8 is required only for mTORC2 signaling, and mTORC2 is a necessary component of the Akt-FOXO and PKCalpha pathways.
- Published
- 2006
19. Autophagy is required for glucose homeostasis and lung tumor maintenance
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Sinan Khor, Jessie Yanxiang Guo, Joshua D. Rabinowitz, Saurabh V. Laddha, Tyler Jacks, Xin Teng, Sandy M. Price, Gizem Karsli-Uzunbas, Eileen White, Nada Y. Kalaany, Chang S. Chan, MIT Kavli Institute for Astrophysics and Space Research, and Jacks, Tyler E.
- Subjects
Cachexia ,Lung Neoplasms ,Biology ,Autophagy-Related Protein 7 ,Article ,Proto-Oncogene Proteins p21(ras) ,Mice ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Autophagy ,Glucose homeostasis ,Animals ,Homeostasis ,Humans ,Lung cancer ,Neurodegeneration ,Cancer ,medicine.disease ,humanities ,Hypoglycemia ,Gene Expression Regulation, Neoplastic ,Glucose ,Oncology ,Cancer research ,Tumor Suppressor Protein p53 ,Microtubule-Associated Proteins - Abstract
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation by activation of oncogenic KrasG12D and deletion of the Trp53 tumor suppressor. Acute autophagy ablation in mice with preexisting NSCLC, however, blocked tumor growth, promoted tumor cell death, and generated more benign disease (oncocytomas). This antitumor activity occurred before destruction of normal tissues, suggesting that acute autophagy inhibition may be therapeutically beneficial in cancer. Significance: We systemically ablated cellular self-cannibalization by autophagy in adult mice and determined that it is dispensable for short-term survival, but required to prevent fatal hypoglycemia and cachexia during fasting, delineating a new role for autophagy in metabolism. Importantly, acute, systemic autophagy ablation was selectively destructive to established tumors compared with normal tissues, thereby providing the preclinical evidence that strategies to inhibit autophagy may be therapeutically advantageous for RAS-driven cancers., Val Skinner Foundation, National Institutes of Health (U.S.) (RC1 CA147961), Rutgers Cancer Institute of New Jersey, Rutgers Cancer Institute of New Jersey (P30 CA072720), National Institutes of Health (U.S.) (R01 CA163591), National Institutes of Health (U.S.) (R37 CA53370), National Institutes of Health (U.S.) (R01 CA130893)
- Published
- 2014
20. Abstract IA26: Identifying metabolic liabilities in obesity-associated pancreatic cancer
- Author
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Daniel S. Hitchcock, Nicholas Stylopoulos, Nada Y. Kalaany, Cory D. Dubois, Clary B. Clish, and Tamara Zaytouni
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Cancer Research ,medicine.medical_specialty ,Insulin ,medicine.medical_treatment ,Cancer ,Biology ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Internal medicine ,Pancreatic cancer ,medicine ,Cancer research ,Signal transduction ,Pancreas ,Molecular Biology ,Survival rate ,Protein kinase B ,PI3K/AKT/mTOR pathway - Abstract
Obesity is a rising pandemic that is increasingly being recognized for its striking correlation with the incidence of/mortality from cancers of different tissues, particularly that of the pancreas. Ranking as the fourth leading cause of cancer death in the United States, pancreatic ductal adenocarcinoma (PDAC) is a highly lethal, insidious malignancy whose poor prognosis is reflected in a 5-year survival rate of only 5%. In an obese state characterized by elevated circulating levels of insulin and insulin-like growth factor-1 (IGF-1), metabolic signaling pathways, including PI3K/Akt might be aberrantly regulated, altering tumor cell metabolism and driving the maintenance of PDAC. Recognized as a hallmark of cancer formation, altered cellular metabolism is evident in Kras-driven PDAC tumors. However, the specific metabolic impact of obesity and increased insulin and IGF-1 levels on PDAC tumors has not been thoroughly investigated. We performed a large orthotopic xenograft experiment involving the injection of human pancreatic cancer cells modified to either express constitutively active, myristoylated Akt, or a control fluorescent protein (CFP) into the pancreata of lean or diet-induced obese immunodeficient mice. We find that control CFP-tumors grown in obese mice and all Akt-tumors, independent of obesity, are significantly larger than CFP-tumors grown in lean mice. Gene expression and metabolomics analyses demonstrate a striking representation of distinct metabolic pathways, including the nitrogen/arginine or urea cycle pathway in pancreatic tumors grown in obese versus lean mice. This pathway enrichment partially overlaps with that observed in the Akt-driven tumors, independent of obesity. Here we describe the validation of these results by altering urea cycle gene expression in the human PDAC cells and assessing their effect on PDAC cell proliferation, survival, metabolism, and response to arginine deprivation both in tissue culture in vitro and as orthotopic xenografts in the pancreata of lean or diet-induced obese mice in vivo. These studies will help identify metabolic dependencies in Akt-driven or non-Akt-driven pancreatic tumors grown under either obese/hyperinsulinemic or lean states, that could be targeted therapeutically in PDAC patients. Citation Format: Tamara Zaytouni, Cory Dubois, Daniel Hitchcock, Nicholas Stylopoulos, Clary Clish, Nada Kalaany. Identifying metabolic liabilities in obesity-associated pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA26.
- Published
- 2016
21. Functional genomics reveals serine synthesis is essential in PHGDH-amplified breast cancer
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Michael E. Pacold, Shalini Sethumadhavan, Bingbing Yuan, Yoav D. Shaul, Elena F. Brachtel, Jordi Barretina, Mari Mino-Kenudson, Richard Possemato, David M. Sabatini, Hin-Koon Woo, Kıvanç Birsoy, Nicolas Stransky, Albert M. Chan, Dohoon Kim, Nada Y. Kalaany, Zhi-Yang Tsun, Levi A. Garraway, Glenn S. Cowley, David E. Root, Abhishek K. Jha, Francesca G. Barrett, Edward M. Driggers, Kevin Marks, Hyun Gyung Jang, Walter W. Chen, Kathleen Ottina, Peggy P. Hsu, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Koch Institute for Integrative Cancer Research at MIT, Possemato, Richard, Shaul, Yoav D., Pacold, Michael E., Kim, Dohoon, Birsoy, Kivanc, Chen, Walter W., Tsun, Zhi-Yang, Kalaany, Nada Y., Hsu, Peggy P., Ottina, Kathleen, Chan, Albert M., Yuan, Bingbing B., and Sabatini, David M.
- Subjects
Citric Acid Cycle ,Glutamic Acid ,Breast Neoplasms ,Biology ,medicine.disease_cause ,Gene Expression Regulation, Enzymologic ,Article ,Serine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Breast cancer ,RNA interference ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Phosphoglycerate dehydrogenase ,Melanoma ,Phosphoglycerate Dehydrogenase ,Cell Proliferation ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Cell growth ,Cancer ,Genomics ,medicine.disease ,Molecular biology ,3. Good health ,Gene Expression Regulation, Neoplastic ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,Ketoglutaric Acids ,RNA Interference ,Carcinogenesis ,Neoplasm Transplantation - Abstract
Cancer cells adapt their metabolic processes to drive macromolecular biosynthesis for rapid cell growth and proliferation[superscript 1, 2]. RNA interference (RNAi)-based loss-of-function screening has proven powerful for the identification of new and interesting cancer targets, and recent studies have used this technology in vivo to identify novel tumour suppressor genes[superscript 3]. Here we developed a method for identifying novel cancer targets via negative-selection RNAi screening using a human breast cancer xenograft model at an orthotopic site in the mouse. Using this method, we screened a set of metabolic genes associated with aggressive breast cancer and stemness to identify those required for in vivo tumorigenesis. Among the genes identified, phosphoglycerate dehydrogenase (PHGDH) is in a genomic region of recurrent copy number gain in breast cancer and PHGDH protein levels are elevated in 70% of oestrogen receptor (ER)-negative breast cancers. PHGDH catalyses the first step in the serine biosynthesis pathway, and breast cancer cells with high PHGDH expression have increased serine synthesis flux. Suppression of PHGDH in cell lines with elevated PHGDH expression, but not in those without, causes a strong decrease in cell proliferation and a reduction in serine synthesis. We find that PHGDH suppression does not affect intracellular serine levels, but causes a drop in the levels of α-ketoglutarate, another output of the pathway and a tricarboxylic acid (TCA) cycle intermediate. In cells with high PHGDH expression, the serine synthesis pathway contributes approximately 50% of the total anaplerotic flux of glutamine into the TCA cycle. These results reveal that certain breast cancers are dependent upon increased serine pathway flux caused by PHGDH overexpression and demonstrate the utility of in vivo negative-selection RNAi screens for finding potential anticancer targets., Susan G. Komen Breast Cancer Foundation (Fellowship), Life Sciences Research Foundation (Fellowship), W. M. Keck Foundation, David H. Koch Cancer Research Fund, Alexander and Margaret Stewart Trust, National Institutes of Health (U.S.) (Grant CA103866)
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- 2010
22. Tumours with PI3K activation are resistant to dietary restriction
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David M. Sabatini and Nada Y. Kalaany
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Male ,PTEN ,caspase-3 ,medicine.medical_treatment ,Gene Expression ,Apoptosis ,Mice, SCID ,PI3K ,Prostate cancer ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Mice, Inbred NOD ,Neoplasms ,0303 health sciences ,Multidisciplinary ,Forkhead Box Protein O1 ,Forkhead Transcription Factors ,3. Good health ,030220 oncology & carcinogenesis ,IGF-1 ,Ki-67 ,Female ,Signal Transduction ,insulin ,medicine.medical_specialty ,Transplantation, Heterologous ,Biology ,Article ,03 medical and health sciences ,Internal medicine ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Lung cancer ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Caloric Restriction ,Akt ,Growth factor ,PTEN Phosphohydrolase ,Cancer ,medicine.disease ,Enzyme Activation ,Endocrinology ,Cell culture ,Cancer cell ,biology.protein ,FOXO ,RAS - Abstract
Dietary restriction delays the incidence and decreases the growth of various types of tumours, but the mechanisms underlying the sensitivity of tumours to food restriction remain unknown. Here we show that certain human cancer cell lines, when grown as tumour xenografts in mice, are highly sensitive to the anti-growth effects of dietary restriction, whereas others are resistant. Cancer cells that form dietary-restriction-resistant tumours carry mutations that cause constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway and in culture proliferate in the absence of insulin or insulin-like growth factor 1. Substitution of an activated mutant allele of PI3K with wild-type PI3K in otherwise isogenic cancer cells, or the restoration of PTEN expression in a PTEN-null cancer cell line, is sufficient to convert a dietary-restriction-resistant tumour into one that is dietary-restriction-sensitive. Dietary restriction does not affect a PTEN-null mouse model of prostate cancer, but it significantly decreases tumour burden in a mouse model of lung cancer lacking constitutive PI3K signalling. Thus, the PI3K pathway is an important determinant of the sensitivity of tumours to dietary restriction, and activating mutations in the pathway may influence the response of cancers to dietary restriction-mimetic therapies.
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- 2008
23. ECM-induced gap junctional communication enhances mammary epithelial cell differentiation
- Author
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Myriam H. Daher, Nada Y. Kalaany, Rabih S. Talhouk, Marwan El-Sabban, Agnel Sfeir, and Rola A. Bassam
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Integrin ,Cell Communication ,Biology ,Connexins ,Extracellular matrix ,chemistry.chemical_compound ,Mice ,Downregulation and upregulation ,medicine ,Cyclic AMP ,Animals ,Antibodies, Blocking ,Cells, Cultured ,Polyhydroxyethyl Methacrylate ,Epithelial cell differentiation ,Basement membrane ,Lucifer yellow ,Integrin beta1 ,Cell Membrane ,Gap junction ,Caseins ,Gap Junctions ,Cell Differentiation ,Cell Biology ,Isoquinolines ,Immunohistochemistry ,Cell biology ,Extracellular Matrix ,Connexin 26 ,medicine.anatomical_structure ,chemistry ,Connexin 43 ,biology.protein ,Glycyrrhetinic Acid ,Female ,Intracellular - Abstract
The relationship between gap junctional intercellular communication (GJIC) and mammary cell (CID-9) differentiation in vitro was explored. CID-9 cells differentiate and express beta-casein in an extracellular matrix (ECM)- and hormone-dependent manner. In response to interaction with the ECM, cells in culture modulated the expression of their gap junction proteins at the transcriptional and post-translational levels. In the presence of EHS-matrix, connexins (Cx)26, 32 and 43 localized predominantly to the plasma membrane, and enhanced GJIC [as measured by Lucifer Yellow (LY) dye transfer assays] was noted. Inhibition of GJIC of cells on EHS-matrix with 18 alpha glycyrrhetinic acid (GA) resulted in reversible downregulation of beta-casein expression. In the presence of cAMP, cells cultured on plastic expressed beta-casein, upregulated Cx43 and Cx26 protein levels and enhanced GJIC. This was reversed in the presence of 18 alpha GA. cAMP-treated cells plated either on a non-adhesive PolyHEMA substratum or on plastic supplemented with function-blocking anti-beta 1 integrin antibodies, maintained beta-casein expression. These studies suggest that cell-ECM interaction alone may induce differentiation through changes in cAMP levels and formation of functional gap junctions. That these events are downstream of ECM signalling was underscored by the fact that enhanced GJIC induced partial differentiation in mammary epithelial cells in the absence of an exogenously provided basement membrane and in a beta 1-integrin- and adhesion-independent manner.
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- 2003
24. Abstract 4317: PTEN-null tumors cohabiting the same lung display differential Akt activation and sensitivity to dietary restriction
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Vedat O. Yilmaz, Jade Moon, David M. Sabatini, Nada Y. Kalaany, Ömer H. Yilmaz, Trudy G. Oliver, Mari Mino-Kenudson, Natasha L. Curry, and Tyler Jacks
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Cancer Research ,medicine.medical_specialty ,biology ,Cancer ,medicine.disease ,Endocrinology ,Oncology ,Growth factor receptor ,Internal medicine ,Genotype ,medicine ,biology.protein ,Cancer research ,PTEN ,Lung cancer ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Insulin-like growth factor 1 receptor - Abstract
PTEN loss is considered a biomarker for activated PI3K/Akt, a pathway frequently mutated in cancer, and recently shown to confer resistance to dietary restriction (DR). Here we demonstrate that PTEN loss is not sufficient to drive Akt activation and resistance to DR in tumors with low growth factor receptor levels. We describe a murine PTEN-null Kras-driven lung cancer model that harbors both DR-resistant, higher-grade, bronchiolar tumors with high-Akt-activity, and DR-sensitive, lower-grade, alveolar tumors with low-Akt-activity. We find that this phenotype is cell-autonomous and that normal bronchiolar cells express higher levels of IGF1R and ENTPD5, an endoplasmic reticulum (ER) enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF1R levels and sensitize bronchiolar tumor cells to serum in vitro and to DR in vivo. Furthermore, we find that a significant percentage of human non-small cell lung cancer (NSCLC) have low Akt activity despite PTEN loss. Our studies point to a heterogeneity of Akt activation in the same murine PTEN-null lung tissue, as well as in human NSCLC, underscoring the challenges facing personalized cancer therapy based solely on cancer genotype. They further indicate that the tumor response to anti-cancer therapies, including DR, needs to be based upon PI3K/Akt activity per se, rather than genetic alterations in the PTEN/Akt pathway. Citation Format: Natasha L. Curry, Mari Mino-Kenudson, Trudy G. Oliver, Omer H. Yilmaz, Vedat O. Yilmaz, Jade Moon, Tyler Jacks, David M. Sabatini, Nada Y. Kalaany. PTEN-null tumors cohabiting the same lung display differential Akt activation and sensitivity to dietary restriction. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4317. doi:10.1158/1538-7445.AM2013-4317
- Published
- 2013
25. LXRs regulate the balance between fat storage and oxidation
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Nada Y. Kalaany, Karine Gauthier, David J. Mangelsdorf, Tatsuya Kitazume, Julian A. Peterson, Jay D. Horton, Antonio C. Bianco, Pradeep P.A. Mammen, Daniel J. Garry, and Ann Marie Zavacki
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medicine.medical_specialty ,Physiology ,Receptors, Cytoplasmic and Nuclear ,Adipose tissue ,Hyperlipidemias ,Oxidative phosphorylation ,digestive system ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,polycyclic compounds ,Animals ,Obesity ,Receptor ,Liver X receptor ,Molecular Biology ,Liver X Receptors ,030304 developmental biology ,Mice, Knockout ,0303 health sciences ,Chemistry ,Cholesterol ,Lipid metabolism ,Cell Biology ,Lipid Metabolism ,Orphan Nuclear Receptors ,DNA-Binding Proteins ,Endocrinology ,Adipose Tissue ,Liver ,Lipogenesis ,lipids (amino acids, peptides, and proteins) ,Lipid Peroxidation ,Insulin Resistance ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Transcription Factors ,Hormone - Abstract
SummaryDespite the well-established role of liver X receptors (LXRs) in regulating cholesterol homeostasis, their contribution to lipid homeostasis remains unclear. Here we show that LXR null mice are defective in hepatic lipid metabolism and are resistant to obesity when challenged with a diet containing both high fat and cholesterol. This phenotype is dependent on the presence of dietary cholesterol and is accompanied by the aberrant production of thyroid hormone in liver. Interestingly, the inability of LXR−/− mice to induce SREBP-1c-dependent lipogenesis does not explain the LXR−/− phenotype, since SREBP-1c null mice are not obesity resistant. Instead, the LXR−/− response is due to abnormal energy dissipation resulting from uncoupled oxidative phosphorylation and ectopic expression of uncoupling proteins in muscle and white adipose. These studies suggest that, by selectively sensing the cholesterol component of a lipid-rich diet, LXRs govern the balance between storage and oxidation of dietary fat.
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