Do the downloads!! Share!! The diffusion of very important information and knowledge is essential for the world progress always!! Thanks!!
- – > Mestrado – Dissertation – Tabelas, Figuras e Gráficos – Tables, Figures and Graphics – ´´My´´ Dissertation @ #Innovation #energy #life #health #Countries #Time #Researches #Reference #Graphics #Ages #Age #Mice #People #Person #Mouse #Genetics #PersonalizedMedicine #Diagnosis #Prognosis #Treatment #Disease #UnknownDiseases #Future #VeryEfficientDrugs #VeryEfficientVaccines #VeryEfficientTherapeuticalSubstances #Tests #Laboratories #Investments #Details #HumanLongevity #DNA #Cell #Memory #Physiology #Nanomedicine #Nanotechnology #Biochemistry #NewMedicalDevices #GeneticEngineering #Internet #History #Science #World
The influence of physical activity in the progression of experimental lung cancer in mice
- PMID: 22683274
- DOI: 10.1016/j.prp.2012.04.006
GRUPO_AF1 – GROUP AFA1 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 1 – GROUP AFAN1 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO_AF2 – GROUP AFA2 – Aerobic Physical Activity – Atividade Física Aeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
GRUPO AFAN 2 – GROUP AFAN 2 – Anaerobic Physical Activity – Atividade Física Anaeróbia – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
Slides – mestrado – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
DMBA CARCINOGEN IN EXPERIMENTAL MODELS
Avaliação da influência da atividade física aeróbia e anaeróbia na progressão do câncer de pulmão experimental – Summary – Resumo – ´´My´´ Dissertation – Faculty of Medicine of Sao Jose do Rio Preto
Lung cancer is one of the most incident neoplasms in the world, representing the main cause of mortality for cancer. Many epidemiologic studies have suggested that physical activity may reduce the risk of lung cancer, other works evaluate the effectiveness of the use of the physical activity in the suppression, remission and reduction of the recurrence of tumors. The aim of this study was to evaluate the effects of aerobic and anaerobic physical activity in the development and the progression of lung cancer. Lung tumors were induced with a dose of 3mg of urethane/kg, in 67 male Balb – C type mice, divided in three groups: group 1_24 mice treated with urethane and without physical activity; group 2_25 mice with urethane and subjected to aerobic swimming free exercise; group 3_18 mice with urethane, subjected to anaerobic swimming exercise with gradual loading 5-20% of body weight. All the animals were sacrificed after 20 weeks, and lung lesions were analyzed. The median number of lesions (nodules and hyperplasia) was 3.0 for group 1, 2.0 for group 2 and 1.5-3 (p=0.052). When comparing only the presence or absence of lesion, there was a decrease in the number of lesions in group 3 as compared with group 1 (p=0.03) but not in relation to group 2. There were no metastases or other changes in other organs. The anaerobic physical activity, but not aerobic, diminishes the incidence of experimental lung tumors.
Copyright © 2012 Elsevier GmbH. All rights reserved.
@ ´´Harvard is a founding member of the Association of American Universities and remains a preeminent research university with “very high” research activity (R1) and comprehensive doctoral programs across the arts, sciences, engineering, and medicine according to the Carnegie Classification. With Harvard Medical School consistently ranking first among medical schools for research, biomedical research is an area of particular strength for the university. More than 11,000 faculty members and over 1,600 medical and graduate students contribute to discovery and innovation at Harvard Medical School as well as its 15 affiliated hospitals and research institutes. Harvard Medical School and its affiliates attracted $1.65 billion in competitive research grants from the National Institutes of Health in 2019, more than twice as much as any other university.´´
Help us improve our products. Sign up to take part.
a nature research journalMENU
High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy
- Xiangyu Zhang,
- Ismail Sergin,
- Trent D. Evans,
- Se-Jin Jeong,
- Astrid Rodriguez-Velez,
- Divya Kapoor,
- Sunny Chen,
- Eric Song,
- Karyn B. Holloway,
- Jan R. Crowley,
- Slava Epelman,
- Conrad C. Weihl,
- Abhinav Diwan,
- Daping Fan,
- Bettina Mittendorfer,
- Nathan O. Stitziel,
- Joel D. Schilling,
- Irfan J. Lodhi &
- Babak Razani
- 267 Accesses
- 187 Altmetric
High-protein diets are commonly utilized for weight loss, yet they have been reported to raise cardiovascular risk. The mechanisms underlying this risk are unknown. Here, we show that dietary protein drives atherosclerosis and lesion complexity. Protein ingestion acutely elevates amino acid levels in blood and atherosclerotic plaques, stimulating macrophage mammalian target of rapamycin (mTOR) signalling. This is causal in plaque progression, because the effects of dietary protein are abrogated in macrophage-specific Raptor-null mice. Mechanistically, we find amino acids exacerbate macrophage apoptosis induced by atherogenic lipids, a process that involves mammalian target of rapamycin complex 1 (mTORC1)-dependent inhibition of mitochondrial autophagy (mitophagy), accumulation of dysfunctional mitochondria and mitochondrial apoptosis. Using macrophage-specific mTORC1- and autophagy-deficient mice, we confirm this amino acid–mTORC1–autophagy signalling axis in vivo. Our data provide insights into the deleterious impact of excessive protein ingestion on macrophages and atherosclerotic progression. Incorporation of these concepts in clinical studies is important to define the vascular effects of protein-based weight loss regimens.
Subscribe to Journal
Get full journal access for 1 year
only $8.67 per issueSubscribe
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
from$8.99Rent or Buy
All prices are NET prices.
Additional access options:
The data that support the findings of this study are available from the corresponding author upon request. Source data for Figs. 4 and 8 and Extended Data Figs. 3, 4 and 6 are provided with the paper.
- 1.Moore, K. J. & Tabas, I. Macrophages in the pathogenesis of atherosclerosis. Cell 145, 341–355 (2011).
- 2.Gardner, C. D. et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A to Z Weight Loss Study: a randomized trial. JAMA 297, 969–977 (2007).
- 3.Halton, T. L. et al. Low-carbohydrate-diet score and the risk of coronary heart disease in women. N. Engl. J. Med. 355, 1991–2002 (2006).
- 4.Hu, F. B. et al. Dietary protein and risk of ischemic heart disease in women. Am. J. Clin. Nutr. 70, 221–227 (1999).
- 5.Lagiou, P. et al. Low carbohydrate-high protein diet and incidence of cardiovascular diseases in Swedish women: prospective cohort study. BMJ 344, e4026 (2012).
- 6.Debry, G. Dietary Proteins and Atherosclerosis (CRC Press, 2004).
- 7.Foo, S. Y. et al. Vascular effects of a low-carbohydrate high-protein diet. Proc. Natl Acad. Sci. USA 106, 15418–15423 (2009).
- 8.Wolfson, R. L. & Sabatini, D. M. The dawn of the age of amino acid sensors for the mTORC1 pathway. Cell Metab. 26, 301–309 (2017).
- 9.Ma, Y. et al. A dietary quality comparison of popular weight-loss plans. J. Am. Diet. Assoc. 107, 1786–1791 (2007).
- 10.Anderson, J. W., Konz, E. C. & Jenkins, D. J. Health advantages and disadvantages of weight-reducing diets: a computer analysis and critical review. J. Am. Coll. Nutr. 19, 578–590 (2000).
- 11.Razani, B. et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 15, 534–544 (2012).
- 12.Sergin, I. et al. Inclusion bodies enriched for p62 and polyubiquitinated proteins in macrophages protect against atherosclerosis. Sci. Signal. 9, ra2 (2016).
- 13.Sancak, Y. et al. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141, 290–303 (2010).
- 14.Zoncu, R. et al. mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H+-ATPase. Science 334, 678–683 (2011).
- 15.Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010).
- 16.Ai, D. et al. Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ. Res. 114, 1576–1584 (2014).
- 17.Li, N. et al. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J. Biol. Chem. 278, 8516–8525 (2003).
- 18.Emanuel, R. et al. Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae. Arterioscler. Thromb. Vasc. Biol. 34, 1942–1952 (2014).
- 19.Liao, X. et al. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 15, 545–553 (2012).
- 20.Ouimet, M. et al. Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase. Cell Metab. 13, 655–667 (2011).
- 21.Sergin, I. et al. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nat. Commun. 8, 15750 (2017).
- 22.Evans, T. D., Sergin, I., Zhang, X. & Razani, B. Target acquired: selective autophagy in cardiometabolic disease. Sci. Signal. 10, eaag2298 (2017).
- 23.Sun, N. et al. Measuring in vivo mitophagy. Mol. Cell 60, 685–696 (2015).
- 24.Laplante, M. & Sabatini, D. M. mTOR signaling in growth control and disease. Cell 149, 274–293 (2012).
- 25.Food and Agriculture Organization, Food Policy and Food Science Service, Nutrition Division. Amino-Acid Content of Foods and Biological Data on Proteins (FAO, 1970).
- 26.Castellano, B. M. et al. Lysosomal cholesterol activates mTORC1 via an SLC38A9–Niemann-Pick C1 signaling complex. Science 355, 1306–1311 (2017).
- 27.Bernstein, A. M. et al. Major dietary protein sources and risk of coronary heart disease in women. Circulation 122, 876–883 (2010).
- 28.Solon-Biet, S. M. et al. The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab. 19, 418–430 (2014).
- 29.Kurdi, A., De Meyer, G. R. & Martinet, W. Potential therapeutic effects of mTOR inhibition in atherosclerosis. Br. J. Clin. Pharmacol. 82, 1267–1279 (2016).
- 30.Hara, T. et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441, 885–889 (2006).
- 31.Razani, B. et al. Fatty acid synthase modulates homeostatic responses to myocardial stress. J. Biol. Chem. 286, 30949–30961 (2011).
- 32.Jewell, J. L. et al. Metabolism. Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194–198 (2015).
- 33.Febbraio, M. et al. Targeted disruption of the class B scavenger receptor CD36 protects against atherosclerotic lesion development in mice. J. Clin. Invest. 105, 1049–1056 (2000).
- 34.Razani, B. et al. Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J. Biol. Chem. 276, 38121–38138 (2001).
- 35.Katayama, H., Kogure, T., Mizushima, N., Yoshimori, T. & Miyawaki, A. A sensitive and quantitative technique for detecting autophagic events based on lysosomal delivery. Chem. Biol. 18, 1042–1052 (2011).
- 36.Sun, N. et al. A fluorescence-based imaging method to measure in vitro and in vivo mitophagy using mt-Keima. Nat. Protoc. 12, 1576–1587 (2017).
This work was supported by National Institutes of Health grant no. R01 HL125838, VA MERIT I01 BX003415, American Diabetes Association grant no. 1-18-IBS-029, Washington University Diabetic Cardiovascular Disease Center and Diabetes Research Center grant no. P30 DK020579, Washington University Mass Spectrometry core grant nos. P41GM103422 and P30DK056341, and the Foundation for Barnes-Jewish Hospital.
- Department of Medicine, Cardiovascular Division, Washington University School of Medicine, St Louis, MO, USA
- Xiangyu Zhang
- , Ismail Sergin
- , Trent D. Evans
- , Se-Jin Jeong
- , Astrid Rodriguez-Velez
- , Divya Kapoor
- , Sunny Chen
- , Eric Song
- , Karyn B. Holloway
- , Abhinav Diwan
- , Nathan O. Stitziel
- , Joel D. Schilling
- & Babak Razani
- John Cochran VA Medical Center, St Louis, MO, USA
- Xiangyu Zhang
- , Se-Jin Jeong
- , Divya Kapoor
- , Karyn B. Holloway
- & Abhinav Diwan
- Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St Louis, MO, USA
- Jan R. Crowley
- & Irfan J. Lodhi
- University Health Network, Peter Munk Cardiac Center, University of Toronto, Toronto, Ontario, Canada
- Slava Epelman
- Department of Neurology, Washington University School of Medicine, St Louis, MO, USA
- Conrad C. Weihl
- Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC, USA
- Daping Fan
- Department of Nutrition, Washington University School of Medicine, St Louis, MO, USA
- Bettina Mittendorfer
- & Babak Razani
- Department of Pathology & Immunology, Washington University School of Medicine, St Louis, MO, USA
- Joel D. Schilling
- & Babak Razani
X.Z. and B.R. designed the studies and wrote the manuscript. X.Z., I.S., T.D.E., S.J., A.R., D.K., S.C., E.S., K.B.H. and J.R.C. performed and analysed the experiments. X.Z. and I.S. prepared the figures. D.K., S.E., C.C.W., A.D., D.F., B.M., N.O.S., J.D.S., I.J.L. and B.R. provided the reagents, advised on the experimental design and performed critical reading of the manuscript.
Correspondence to Babak Razani.
The authors declare no competing interests.
Peer review information Primary Handling Editor: Pooja Jha.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended Data Fig. 1 High Protein diets increase atherosclerotic plaque formation and plaque complexity without altering serum metabolites.
(a) Average daily food intake over 1 week for ApoE-KO mice fed a standard Western diet (n = 5) or high protein Western diet (n = 5) (b–d) Cohorts of ApoE-KO mice were placed on a standard Western diet (Std. WD) or high protein Western diet (HP WD) and after 8 weeks, (b) Body composition (fat and lean weights) (Std. WD: n = 4; HP WD: n = 5), (c) glucose tolerance test (GTT) and glucose AUC (Std. WD: n = 7; HP WD: n = 9), and (d) serum cholesterol, glucose, triglycerides, and free fatty acids (Std. WD: n = 11; HP WD: n = 14) were measured. (e) Quantification of atherosclerotic plaque burden using Oil Red O-stained aortic root sections from mice fed standard or high protein Western diets for 16 weeks; representative roots shown on right (Std. WD: n = 12; HP WD: n = 11). (f) Measurements of serum cholesterol in cohorts of ApoE-KO mice after 16 weeks of standard or high protein Western diets (Std WD: n = 6; HP WD: n = 8). (g-i) Plaque composition quantified by immunofluorescence staining of aortic root sections for (g) macrophage (MOMA-2+) (Std. WD: n = 12; HP WD: n = 13), (h) apoptosis (TUNEL+) (Std. WD: n = 13; HP WD: n = 13), (i) and necrotic core (acellular) (Std. WD: n = 13; HP WD: n = 13). For all graphs, data are presented as mean ±SEM. *P < 0.05, **P < 0.01, ***P < 0.001, two-tailed unpaired t-test.
Extended Data Fig. 2 Levels of select L-amino acids in serum, aorta, and splenic macrophages after high protein challenge.
(a) Serum levels of 8 L-amino acids by mass spectrometry from mice fed standard or high protein Western diets for 8 weeks (Std. WD: n = 8; HP WD: n = 8). (b–d) Time course measurement of the levels of 8 L-amino acids in serum (n = 3) (b), splenic macrophages (n = 2) (c), and atherosclerotic aortas (n = 2) (d) by mass spectrometry after high protein gavage. For all graphs, data are presented as mean ±SEM. *P < 0.05, **P < 0.01, ***P < 0.001, two-tailed unpaired t-test for a and one-way ANOVA with Dunnett’s test for b–d.
Extended Data Fig. 3 Leucine is amongst the best amino acid inducers of mTOR signaling in cultured primary macrophages.
(a, b) Immunoblot analysis of thioglycollate-elicited peritoneal macrophages (PMACs) (a) and bone marrow derived macrophages (BMDM) (b) after 30min of incubation with amino acid-free or regular/amino acid-sufficient medium to assess mTORC1 signaling using phospho- and total S6K and S6 levels as readouts. (c) Representative immunofluorescence images of BMDMs after 15min of incubation with amino acid-free or regular/amino acid-sufficient medium to assess co-localization between mTOR and Lamp2. (d, e) Immunoblot analysis of macrophages after 30min of incubation with regular medium or amino acid-free medium with and without 20 different L-amino acids to assess mTORC1 signaling using phospho- and total S6 levels as readouts. Representative blots (d) and quantification of pS6/total S6 ratio for five independent experiments (e). The best three mTOR inducers and three non-inducers are listed at right. (f, g) Immunofluorescence imaging of macrophages after 15min of incubation with regular medium or amino acid-free medium with and without the best three mTOR inducers and non-inducers to assess co-localization between mTOR and Lamp2. Representative images (f) and quantification of the mTOR/Lamp2 co-localization (+aa: n = 42; -aa: n = 74; Leu: n = 26; Arg: n = 38; Glu: n = 12; Gln: n = 34; Phe: n = 37; Thr: n = 43 cells) (g). For all graphs, data are presented as mean ±SEM. Source data
Extended Data Fig. 4 Body weight and common serum metabolites of control and mϕRaptor KO mice fed a standard or LCHP Western diet.
(a) Immunoblot analysis of control and Raptor KO macrophages after 30min of incubation with regular medium or amino acid-free medium with and without leucine to assess mTORC1 activity using phospho- and total S6K and S6 as readouts. (b) Immunofluorescence imaging of macrophages after 15min of incubation with regular medium or amino acid-free medium with and without leucine to assess co-localization between mTOR and Lamp2. Representative images (left) and quantification of the mTOR/Lamp2 co-localization (right) (Control: +aa: n = 42; -aa: n = 52; Leu: n = 44; ATG5 KO: +aa: n = 27; -aa: n = 40; Leu: n = 43 cells). (c) Total body weights of control (n = 22) and mϕRaptor-KO mice (n = 18) (all on ApoE-KO background) fed a standard Western diet for 8 weeks. (d) Measurements of serum cholesterol, glucose, triglycerides, and free fatty acids in control and mϕRaptor-KO mice after 8 weeks of Western diet feeding (n = 15–25 per group). (e) Measurements of serum cholesterol, glucose, triglycerides, and free fatty acids in cohorts of mϕRaptor-KO mice (on ApoE-null background) fed a standard Western diet or high protein Western diet for 8 weeks (n = 15 per group). For all graphs, data are presented as mean ±SEM. *P < 0.05, **P < 0.01, one-way ANOVA with Tukey’s test for b, two-tailed unpaired t-test for c. Source data
Extended Data Fig. 5 Leucine-mediated activation of mTORC1 synergizes with atherogenic lipids to induce mitochondrial-dependent apoptosis in macrophages.
(a, b) Control and Raptor-KO macrophages were treated with vehicle, 500µg/ml cholesterol crystals (CC) with or without leucine and apoptosis assessed by Caspase-3/7 immunofluorescence staining. Shown are (a) representative images and (b) quantification of >103 cells from acquired images (Control: -aa: n = 11; Leu: n = 9; cc: n = 11; cc+Leu: n = 11; Raptor-KO: n = 11 image fields). For all graphs, data are presented as mean ±SEM. *P < 0.05, ***P < 0.001, one-way ANOVA with Tukey’s test.
(a) Immunoblot analysis of phospho- and total ULK1 levels in macrophages incubated with amino acid-free medium with and without leucine for the indicated times. (b, c) The autophagy marker LC3 was evaluated in macrophages incubated with regular medium or amino acid-free medium with and without leucine for 30 minutes using (b) immunoblot analysis or (c) quantification of LC3 intensity (+aa: n = 52; -aa: n = 52; Leu: n = 52 cells) and number of puncta (+aa: n = 97; -aa: n = 87; Leu: n = 97 cells) by immunofluorescence microscopy. (d) Phospho- and total ULK1 levels were determined in Control and Raptor KO macrophages incubated with regular medium or amino acid-free medium with and without leucine for 30 minutes. (e) LC3 levels in control and Raptor KO macrophages incubated with vehicle or 100nM Bafilomycin for 2 hours. (f) LC3 intensity (Control: +aa: n = 39; -aa: n = 27; Leu: n = 30; Raptor-KO: +aa: n = 31; -aa: n = 30; Leu: n = 30 cells) and number of puncta (n = 52 cells/group) were analyzed by immunofluorescence microscopy in control and Raptor KO macrophages incubated with regular medium or amino acid-free medium with and without leucine for 30 minutes. (g) Quantification of LC3 intensity by immunofluorescence microscopy in control and ATG5-KO macrophages incubated with regular medium or amino acid-free medium with and without leucine for 30 minutes (Control: +aa: n = 52; -aa: n = 50; Leu: n = 51; ATG5 KO: +aa: n = 36; -aa: n = 35; Leu: n = 47 cells). (h) ATG5-KO macrophages were co-incubated with vehicle or CC ± leucine and percent of caspase 3/7-positive cells were quantified in >103 cells from acquired images (-aa: n = 13; -aa+cc: n = 11; Leu: n = 10; Leu+ cc.: n = 12 image fields). For all graphs, data presented as mean ±SEM. *P < 0.05, one-way ANOVA with Tukey’s test. Source Data
Extended Data Fig. 7 Common serum metabolites of mϕRaptor-KO and dual mϕRaptor/mϕATG5-KO (DKO) mice fed a standard Western diet.
Measurements of serum cholesterol, glucose, triglycerides, and free fatty acids in cohorts of mϕRaptor-KO (n = 18) and mϕRaptor/ mϕATG5-KO (DKO) mice (n = 14) (all on ApoE-null background) fed a standard Western diet for 8 weeks.
Supplementary Fig. 1
Unprocessed western blots of Fig. 4
Unprocessed western blots of Fig. 8
Unprocessed western blots of Extended Data Fig. 3
Unprocessed western blots of Extended Data Fig. 4
Unprocessed western blots of Extended Data Fig. 6
Rights and permissions
About this article
Cite this article
Zhang, X., Sergin, I., Evans, T.D. et al. High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy. Nat Metab 2, 110–125 (2020). https://doi.org/10.1038/s42255-019-0162-4
- Received18 January 2019
- Accepted13 December 2019
- Published23 January 2020
- Issue DateJanuary 2020
Nature Metabolism | News & Views
- Hanrui Zhang
- & Muredach P. Reilly
- Data availability
- Author information
- Ethics declarations
- Additional information
- Extended data
- Supplementary information
- Source data
- Rights and permissions
- About this article
ISSN 2522-5812 (online)
Publish with us
Libraries & institutions
Advertising & partnerships
© 2020 Springer Nature Limited
- Hangouts-Panel Discussions
- Healthcare News
- Recommend site
Increase in heart attack risk from protein rich diet
- 102 views
- Added Yesterday, 11:55 PM
- Author: newseditor
High-protein diets may help people lose weight and build muscle, but a new study in mice suggests they have a down side: They lead to more plaque in the arteries. Further, the new research shows that high-protein diets spur unstable plaque — the kind most prone to rupturing and causing blocked arteries. More plaque buildup in the arteries, particularly if it’s unstable, increases the risk of heart attack.The new study appears in the journal Nature Metabolism.
“There are clear weight-loss benefits to high-protein diets, which has boosted their popularity in recent years,” said senior author. “But animal studies and some large epidemiological studies in people have linked high dietary protein to cardiovascular problems. We decided to take a look at whether there is truly a causal link between high dietary protein and poorer cardiovascular health.”
The researchers studied mice fed a high-fat diet to deliberately induce atherosclerosis, or plaque buildup in the arteries. According to the senior author, mice must eat a high-fat diet to develop arterial plaque. Therefore, some of the mice received a high-fat diet that was also high in protein. And others were fed a high-fat, low-protein diet for comparison.
“A couple of scoops of protein powder in a milkshake or a smoothie adds something like 40 grams of protein — almost equivalent to the daily recommended intake,” the senior author said. “To see if protein has an effect on cardiovascular health, we tripled the amount of protein that the mice receive in the high-fat, high-protein diet — keeping the fat constant. Protein went from 15% to 46% of calories for these mice.”
The mice on the high-fat, high-protein diet developed worse atherosclerosis — about 30% more plaque in the arteries — than mice on the high-fat, normal-protein diet, despite the fact that the mice eating more protein did not gain weight, unlike the mice on the high-fat, normal-protein diet.
“This study is not the first to show a telltale increase in plaque with high-protein diets, but it offers a deeper understanding of the impact of high protein with the detailed analysis of the plaques,” the senior author said. “In other words, our study shows how and why dietary protein leads to the development of unstable plaques.”
Plaque contains a mix of fat, cholesterol, calcium deposits and dead cells. Past work by the team and other groups has shown that immune cells called macrophages work to clean up plaque in arteries. But the environment inside plaque can overwhelm these cells, and when such cells die, they make the problem worse, contributing to plaque buildup and increasing plaque complexity.
“In mice on the high-protein diet, their plaques were a macrophage graveyard,” the senior author said. “Many dead cells in the core of the plaque make it extremely unstable and prone to rupture. As blood flows past the plaque, that force — especially in the context of high blood pressure — puts a lot of stress on it. This situation is a recipe for a heart attack.”
To understand how high dietary protein might increase plaque complexity, the authors studied the path protein takes after it has been digested — broken down into its original building blocks, called amino acids.
The team found that excess amino acids from a high-protein diet activate a protein in macrophages called mTOR, which tells the cell to grow rather than go about its housecleaning tasks. The signals from mTOR shut down the cells’ ability to clean up the toxic waste of the plaque, and this sets off a chain of events that results in macrophage death. The researchers found that certain amino acids, especially leucine and arginine, were more potent in activating mTOR — and derailing macrophages from their cleanup duties, leading to cell death — than other amino acids.
“Leucine is particularly high in red meat, compared with, say, fish or plant sources of protein,” the senior author said. “A future study might look at high-protein diets with different amino acid contents to see if that could have an effect on plaque complexity. Cell death is the key feature of plaque instability. If you could stop these cells from dying, you might not make the plaque smaller, but you would reduce its instability.
“This work not only defines the critical processes underlying the cardiovascular risks of dietary protein but also lays the groundwork for targeting these pathways in treating heart disease,” the author said.
https://www.nature.com/articles/s42255-019-0162-4 Edited January 25th 2020
Other Top Stories
Copyright © (Science Mission) 2015
This website is temporarily unavailable.
We expect to be back shortly, and appreciate your patience.
We are sorry for the inconvenience.