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Gerszten, Robert

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Gerszten

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Gerszten, Robert
Author's Publications: search.filters.isAuthorOfPublication.55d4ad24-4e00-4c7b-8e7e-728ba53512ab

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    Identification of specific metabolic pathways as druggable targets regulating the sensitivity to cyanide poisoning
    (Public Library of Science, 2018) Sips, Patrick Y.; Shi, Xu; Musso, Gabriel; Nath, Anjali; Zhao, Yanbin; Nielson, Jason; Morningstar, Jordan; Kelly, Amy; Mikell, Brittney; Buys, Eva; Bebarta, Vikhyat; Rutter, Jared; Davisson, V. Jo; Mahon, Sari; Brenner, Matthew; Boss, Gerry R.; Peterson, Randall; Gerszten, Robert; MacRae, Calum
    Cyanide is a potent toxic agent, and the few available antidotes are not amenable to rapid deployment in mass exposures. As a result, there are ongoing efforts to exploit different animal models to identify novel countermeasures. We have created a pipeline that combines high-throughput screening in zebrafish with subsequent validation in two mammalian small animal models as well as a porcine large animal model. We found that zebrafish embryos in the first 3 days post fertilization (dpf) are highly resistant to cyanide, becoming progressively more sensitive thereafter. Unbiased analysis of gene expression in response to several hours of ultimately lethal doses of cyanide in both 1 and 7 dpf zebrafish revealed modest changes in iron-related proteins associated with the age-dependent cyanide resistance. Metabolomics measurements demonstrated significant age-dependent differences in energy metabolism during cyanide exposure which prompted us to test modulators of the tricarboxylic acid cycle and related metabolic processes as potential antidotes. In cyanide-sensitive 7 dpf larvae, we identified several such compounds that offer significant protection against cyanide toxicity. Modulators of the pyruvate dehydrogenase complex, as well as the small molecule sodium glyoxylate, consistently protected against cyanide toxicity in 7 dpf zebrafish larvae. Together, our results indicate that the resistance of zebrafish embryos to cyanide toxicity during early development is related to an altered regulation of cellular metabolism, which we propose may be exploited as a potential target for the development of novel antidotes against cyanide poisoning.
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    Programming human pluripotent stem cells into white and brown adipocytes
    (Nature Publishing Group, 2012) Ahfeldt, Tim; Schinzel, Robert T.; Lee, Youn-Kyoung; Hendrickson, David Gillis; Kaplan, Adam; Lum, David H.; Camahort, Raymond; Xia, Fang; Shay, Jennifer B.; Rhee, Eugene; Clish, Clary B.; Deo, Rahul C.; Shen, Tony; Lau, Frank; Cowley, Alicia; Mowrer, Greg; Al-Siddiqi, Heba; Nahrendorf, Matthias; Musunuru, Kiran; Gerszten, Robert; Rinn, John; Cowan, Chad
    The utility of human pluripotent stem cells is dependent on efficient differentiation protocols that convert these cells into relevant adult cell types. Here we report the robust and efficient differentiation of human pluripotent stem cells into white or brown adipocytes. We found that inducible expression of PPARG2 alone or combined with CEBPB and/or PRDM16 in mesenchymal progenitor cells derived from pluripotent stem cells programmed their development towards a white or brown adipocyte cell fate with efficiencies of 85%–90%. These adipocytes retained their identity independent of transgene expression, could be maintained in culture for several weeks, expressed mature markers and had mature functional properties such as lipid catabolism and insulin-responsiveness. When transplanted into mice, the programmed cells gave rise to ectopic fat pads with the morphological and functional characteristics of white or brown adipose tissue. These results indicate that the cells could be used to faithfully model human disease.
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    β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors
    (Elsevier BV, 2014) Roberts, Lee D.; Boström, Pontus; O’Sullivan, John F.; Schinzel, Robert T.; Lewis, Gregory; Dejam, Andre; Lee, Youn-Kyoung; Palma, Melinda J.; Calhoun, Sondra; Georgiadi, Anastasia; Chen, Ming-Huei; Ramachandran, Vasan S.; Larson, Martin G.; Bouchard, Claude; Rankinen, Tuomo; Souza, Amanda L.; Clish, Clary B.; Wang, Thomas J.; Estall, Jennifer L.; Soukas, Alexander; Cowan, Chad; Spiegelman, Bruce; Gerszten, Robert
    The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.
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    Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients Treated With Anthracyclines, Taxanes, and Trastuzumab
    (Ovid Technologies (Wolters Kluwer Health), 2012) Sawaya, H.; Sebag, I. A.; Plana, J. C.; Januzzi, James; Ky, B.; Tan, T. C.; Cohen, V.; Banchs, J.; Carver, J. R.; Wiegers, S. E.; Martin, R. P.; Picard, Michael; Gerszten, Robert; Halpern, Elkan F.; Passeri, Jonathan; Kuter, Irene; Scherrer-Crosbie, Marielle
    Background: Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab. Methods and Results: Eighty-one women with newly diagnosed human epidermal growth factor receptor 2–positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro–B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, [22%–43%]) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, [2%–14%]) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure. Conclusions: In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.
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    The genetic architecture of NAFLD among inbred strains of mice
    (eLife Sciences Publications, Ltd, 2015) Hui, Simon T; Parks, Brian W; Org, Elin; Norheim, Frode; Che, Nam; Pan, Calvin; Castellani, Lawrence W; Charugundla, Sarada; Dirks, Darwin L; Psychogios, Nikolaos; Neuhaus, Isaac; Gerszten, Robert; Kirchgessner, Todd; Gargalovic, Peter S; Lusis, Aldons J
    To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A >30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis. DOI: http://dx.doi.org/10.7554/eLife.05607.001
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    Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy
    (Elsevier BV, 2013) Loffredo, F; Steinhauser, Matthew; Jay, Steven M.; Gannon, Joseph; Pancoast, James R.; Yalamanchi, Pratyusha; Sinha, Manisha; Dall’Osso, Claudia; Khong, Danika; Shadrach, Jennifer; Miller, Christine; Singer, Britta S.; Stewart, Alex; Psychogios, Nikolaos; Gerszten, Robert; Hartigan, Adam J.; Kim, Mi-Jeong; Serwold, Thomas; Wagers, Amy; Lee, Richard
    The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-b superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.
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    Metabolite Profiles Predict Acute Kidney Injury and Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement
    (John Wiley and Sons Inc., 2016) Elmariah, Sammy; Farrell, Laurie A.; Daher, Maureen; Shi, Xu; Keyes, Michelle J.; Cain, Carolyn H.; Pomerantsev, Eugene; Vlahakes, Gus; Inglessis, Ignacio; Passeri, Jonathan; Palacios, Igor; Fox, Caroline S.; Rhee, Eugene; Gerszten, Robert
    Background: Acute kidney injury (AKI) occurs commonly after transcatheter aortic valve replacement (TAVR) and is associated with markedly increased postoperative mortality. We previously identified plasma metabolites predictive of incident chronic kidney disease, but whether metabolite profiles can identify those at risk of AKI is unknown. Methods and Results: We performed liquid chromatography–mass spectrometry–based metabolite profiling on plasma from patients undergoing TAVR and subjects from the community‐based Framingham Heart Study (N=2164). AKI was defined by using the Valve Academic Research Consortium‐2 criteria. Of 44 patients (mean age 82±9 years, 52% female) undergoing TAVR, 22 (50%) had chronic kidney disease and 9 (20%) developed AKI. Of 85 metabolites profiled, we detected markedly concordant cross‐sectional metabolic changes associated with chronic kidney disease in the hospital‐based TAVR and Framingham Heart Study cohorts. Baseline levels of 5‐adenosylhomocysteine predicted AKI after TAVR, despite adjustment for baseline glomerular filtration rate (odds ratio per 1‐SD increase 5.97, 95% CI 1.62–22.0; P=0.007). Of the patients who had AKI, 6 (66.7%) subsequently died, compared with 3 (8.6%) deaths among those patients who did not develop AKI (P=0.0008) over a median follow‐up of 7.8 months. 5‐adenosylhomocysteine was predictive of all‐cause mortality after TAVR (hazard ratio per 1‐SD increase 2.96, 95% CI 1.33–6.58; P=0.008), independent of baseline glomerular filtration rate. Conclusions: In an elderly population with severe aortic stenosis undergoing TAVR, metabolite profiling improves the prediction of AKI. Given the multifactorial nature of AKI after TAVR, metabolite profiles may identify those patients with reduced renal reserve.
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    Metabolite Profiles During Oral Glucose Challenge
    (American Diabetes Association, 2013) Ho, Jennifer E.; Larson, Martin G.; Vasan, Ramachandran S.; Ghorbani, Anahita; Cheng, Susan; Rhee, Eugene; Florez, Jose; Clish, Clary B.; Gerszten, Robert; Wang, Thomas
    To identify distinct biological pathways of glucose metabolism, we conducted a systematic evaluation of biochemical changes after an oral glucose tolerance test (OGTT) in a community-based population. Metabolic profiling was performed on 377 nondiabetic Framingham Offspring cohort participants (mean age 57 years, 42% women, BMI 30 kg/m2) before and after OGTT. Changes in metabolite levels were evaluated with paired Student t tests, cluster-based analyses, and multivariable linear regression to examine differences associated with insulin resistance. Of 110 metabolites tested, 91 significantly changed with OGTT (P ≤ 0.0005 for all). Amino acids, β-hydroxybutyrate, and tricarboxylic acid cycle intermediates decreased after OGTT, and glycolysis products increased, consistent with physiological insulin actions. Other pathways affected by OGTT included decreases in serotonin derivatives, urea cycle metabolites, and B vitamins. We also observed an increase in conjugated, and a decrease in unconjugated, bile acids. Changes in β-hydroxybutyrate, isoleucine, lactate, and pyridoxate were blunted in those with insulin resistance. Our findings demonstrate changes in 91 metabolites representing distinct biological pathways that are perturbed in response to an OGTT. We also identify metabolite responses that distinguish individuals with and without insulin resistance. These findings suggest that unique metabolic phenotypes can be unmasked by OGTT in the prediabetic state.
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    Early Detection and Prediction of Cardiotoxicity in Chemotherapy-Treated Patients
    (Elsevier BV, 2011) Sawaya, Heloisa; Sebag, Igal A.; Plana, Juan Carlos; Januzzi, James; Ky, Bonnie; Cohen, Victor; Gosavi, Sucheta; Carver, Joseph R.; Wiegers, Susan E.; Martin, Randolph P.; Picard, Michael; Gerszten, Robert; Halpern, Elkan F.; Passeri, Jonathan; Kuter, Irene; Scherrer-Crosbie, Marielle
    As breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro–B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro–B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality.
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    Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis
    (Springer Nature, 2015) Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis; Kathiresan, Sekar; Cohen, David E.; Whetstine, Johnathan; Chung, Raymond; Fernández-Hernando, Carlos; Kaplan, Lee; Bernards, Andre; Gerszten, Robert; Naar, Anders
    Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.