Identification of a leucine-mediated

Fan, J. et al. Rabbit models for the study of human atherosclerosis: from pathophysiological mechanisms to translational medicine. Pharmacol. Ther. 146, 104–119 (2015).

Article 
CAS 
PubMed 

Google Scholar 

Debry, G. Dietary Proteins and Atherosclerosis 1st edn https://doi.org/10.1201/9780203009307 (Taylor & Francis, 2003).

Zhang, X. et al. High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy. Nat. Metab. 2, 110–125 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43–48 (2016).

Article 
ADS 
CAS 
PubMed 

Google Scholar 

Saxton, R. A., Chantranupong, L., Knockenhauer, K. E., Schwartz, T. U. & Sabatini, D. M. Mechanism of arginine sensing by CASTOR1 upstream of mTORC1. Nature 536, 229–233 (2016).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Goberdhan, D. C. I., Wilson, C. & Harris, A. L. Amino acid sensing by mTORC1: intracellular transporters mark the spot. Cell Metab. 23, 580–589 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (The National Academies Press, 2005).

Bauer, J. et al. Evidence-based recommendations for optimal dietary protein intake in older people: a position paper from the prot-age study group. J. Am. Med. Dir. Assoc. 14, 542–559 (2013).

Article 
PubMed 

Google Scholar 

Rizzoli, R., Biver, E. & Brennan-Speranza, T. C. Nutritional intake and bone health. Lancet Diabetes Endocrinol. 9, 606–621 (2021).

Article 
CAS 
PubMed 

Google Scholar 

Berryman, C. E., Lieberman, H. R., Fulgoni, V. L. & Pasiakos, S. M. Protein intake trends and conformity with the dietary reference intakes in the United States: analysis of the National Health and Nutrition Examination Survey, 2001–2014. Am. J. Clin. Nutr. 108, 405–413 (2018).

Article 
PubMed 

Google Scholar 

Mangano, K. M. et al. Dietary protein is associated with musculoskeletal health independently of dietary pattern: the Framingham Third Generation Study. Am. J. Clin. Nutr. 105, 714–722 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Anderson, J. J. et al. Adiposity among 132 479 UK Biobank participants; contribution of sugar intake vs other macronutrients. Int. J. Epidemiol. 46, 492–501 (2017).

ADS 
CAS 
PubMed 

Google Scholar 

Lieberman, H. R., Fulgoni, V. L., Agarwal, S., Pasiakos, S. M. & Berryman, C. E. Protein intake is more stable than carbohydrate or fat intake across various US demographic groups and international populations. Am. J. Clin. Nutr. 112, 180–186 (2020).

Article 
PubMed 
PubMed Central 

Google Scholar 

Millward, D. J. Nutrition and sarcopenia: evidence for an interaction. Proc. Nutr. Soc. 71, 566–575 (2012).

Article 
CAS 
PubMed 

Google Scholar 

Fabek, H. et al. An examination of contributions of animal- and plant-based dietary patterns on the nutrient quality of diets of adult Canadians. Appl. Physiol. Nutr. Metab. 46, 877–886 (2021).

Article 
CAS 
PubMed 

Google Scholar 

Chen, Z. et al. Dietary protein intake and all-cause and cause-specific mortality: results from the Rotterdam Study and a meta-analysis of prospective cohort studies. Eur. J. Epidemiol. 35, 411–429 (2020).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Aggarwal, A. & Drewnowski, A. Plant- and animal-protein diets in relation to sociodemographic drivers, quality, and cost: fFindings from the Seattle Obesity Study. Am. J. Clin. Nutr. 110, 451–460 (2019).

Article 
PubMed 
PubMed Central 

Google Scholar 

Lin, Y. et al. Plant and animal protein intake and its association with overweight and obesity among the Belgian population. Br. J. Nutr. 105, 1106–1116 (2011).

Article 
CAS 
PubMed 

Google Scholar 

Van Nielen, M. et al. Dietary protein intake and incidence of type 2 diabetes in Europe: the EPIC-InterAct case-cohort study. Diabetes Care 37, 1854–1862 (2014).

Article 
PubMed 

Google Scholar 

Johnston, B. C. et al. Unprocessed red meat and processed meat consumption: dietary guideline recommendations from the nutritional recommendations (NUTRIRECS) consortium. Ann. Intern. Med. 171, 756–764 (2019).

Article 
PubMed 

Google Scholar 

Song, M. et al. Association of animal and plant protein intake with all-cause and cause-specific mortality. JAMA Intern. Med. 179, 1509–1518 (2016).

Google Scholar 

Woollard, K. J. & Geissmann, F. Monocytes in atherosclerosis: subsets and functions. Nat. Rev. Cardiol. 7, 77–86 (2010).

Article 
PubMed 
PubMed Central 

Google Scholar 

Ghattas, A., Griffiths, H. R., Devitt, A., Lip, G. Y. H. & Shantsila, E. Monocytes in coronary artery disease and atherosclerosis: where are we now? J. Am. Coll. Cardiol. 62, 1541–1551 (2013).

Article 
CAS 
PubMed 

Google Scholar 

Hilgendorf, I., Swirski, F. K. & Robbins, C. S. Monocyte fate in atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 35, 272–279 (2015).

Article 
CAS 
PubMed 

Google Scholar 

Bzowska, M. et al. Oxidized LDLs inhibit TLR-induced IL-10 production by monocytes: a new aspect of pathogen-accelerated atherosclerosis. Inflammation 35, 1567–1584 (2012).

Article 
CAS 
PubMed 

Google Scholar 

Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy. https://doi.org/10.1080/15548627.2020.1797280 (2021).

Van der Vieren, M. et al. A novel leukointegrin, αdβ2, binds preferentially to ICAM-3. Immunity 3, 683–690 (1995).

Article 
PubMed 

Google Scholar 

Podolnikova, N. P., Kushchayeva, Y. S., Wu, Y. F., Faust, J. & Ugarova, T. P. The role of integrins αMβ2 (Mac-1, CD11b/CD18) and αDβ2 (CD11d/CD18) in macrophage fusion. Am. J. Pathol. 186, 2105–2116 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Chistiakov, D. A., Killingsworth, M. C., Myasoedova, V. A., Orekhov, A. N. & Bobryshev, Y. V. CD68/macrosialin: not just a histochemical marker. Lab. Investig. 97, 4–13 (2017).

Article 
CAS 
PubMed 

Google Scholar 

Jewell, J. L. et al. Differential regulation of mTORC1 by leucine and glutamine. Science 347, 194–198 (2015).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Atherton, P. J., Smith, K., Etheridge, T., Rankin, D. & Rennie, M. J. Distinct anabolic signalling responses to amino acids in C2C12 skeletal muscle cells. Amino Acids 38, 1533–1539 (2010).

Article 
CAS 
PubMed 

Google Scholar 

Yin, S. et al. Vascular effects of a low-carbohydrate high-protein diet. Proc. Natl Acad. Sci. USA 106, 1–6 (2009).

Google Scholar 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Mu, W. C., Vanhoosier, E., Elks, C. M. & Grant, R. W. Long-term effects of dietary protein and branched-chain amino acids on metabolism and inflammation in mice. Nutrients 10, 918 (2018).

Article 
PubMed 
PubMed Central 

Google Scholar 

Yap, Y. W. et al. Restriction of essential amino acids dictates the systemic metabolic response to dietary protein dilution. Nat. Commun. 11, 2894 (2020).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Maida, A. et al. Repletion of branched chain amino acids reverses mTORC1 signaling but not improved metabolism during dietary protein dilution. Mol. Metab. 6, 873–881 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Fontana, L. et al. Decreased Consumption of branched-chain amino acids improves metabolic health. Cell Rep. 16, 520–530 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Roth, G. A. et al. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736–1788 (2018).

Article 

Google Scholar 

Laslett, L. J. et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College Of Cardiology. J. Am. Coll. Cardiol. 60, S1–S49 (2012).

Article 
PubMed 

Google Scholar 

Virani, S. S. et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation 141, e139–e596 (2020).

Article 
PubMed 

Google Scholar 

Green, C. L. & Lamming, D. W. Regulation of metabolic health by essential dietary amino acids. Mech. Ageing Dev. 177, 186–200 (2019).

Article 
CAS 
PubMed 

Google Scholar 

McGarrah, R. W. & White, P. J. Branched-chain amino acids in cardiovascular disease. Nat. Rev. Cardiol. 20, 77–89 (2023).

Article 
CAS 
PubMed 

Google Scholar 

White, P. J. et al. Insulin action, type 2 diabetes, and branched-chain amino acids: a two-way street. Mol. Metab. 52, 101261 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Yu, D. et al. The adverse metabolic effects of branched-chain amino acids are mediated by isoleucine and valine. Cell Metab. 33, 905–922 (2021).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Deelen, J. et al. A metabolic profile of all-cause mortality risk identified in an observational study of 44,168 individuals. Nat. Commun. 10, 1–8 (2019).

Article 
ADS 

Google Scholar 

Yoon, M. S. mTOR as a key regulator in maintaining skeletal muscle mass. Front. Physiol. 8, 1–9 (2017).

Article 
MathSciNet 
CAS 

Google Scholar 

Layman, D. K. et al. Defining meal requirements for protein to optimize metabolic roles of amino acids. Am. J. Clin. Nutr. 101, 1330S–1338S (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Churchward-Venne, T. A. et al. Supplementation of a suboptimal protein dose with leucine or essential amino acids: effects on myofibrillar protein synthesis at rest and following resistance exercise in men. J. Physiol. 590, 2751–2765 (2012).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Smith, G. I. et al. Protein ingestion induces muscle insulin resistance independent of leucine-mediated mTOR activation. Diabetes 64, 1555–1563 (2015).

Article 
CAS 
PubMed 

Google Scholar 

Mittendorfer, B., Klein, S. & Fontana, L. A word of caution against excessive protein intake. Nat. Rev. Endocrinol. 16, 59–66 (2020).

Article 
PubMed 

Google Scholar 

Paddon-Jones, D., Sheffield-Moore, M., Katsanos, C. S., Zhang, X.J. & Wolfe, R. R. Differential stimulation of muscle protein synthesis in elderly humans following isocaloric ingestion of amino acids or whey protein. Exp. Gerontol. 41, 215–219 (2006).

Article 
CAS 
PubMed 

Google Scholar 

Deutz, N. E. P. et al. Protein intake and exercise for optimal muscle function with aging: recommendations from the ESPEN Expert Group. Clin. Nutr. 33, 929–936 (2014).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Drummen, M., Tischmann, L., Gatta-Cherifi, B., Adam, T. & Westerterp-Plantenga, M. Dietary protein and energy balance in relation to obesity and co-morbidities. Front. Endocrinol. 9, 1–13 (2018).

Article 

Google Scholar 

Magkos, F. The role of dietary protein in obesity. Rev. Endocr. Metab. Disord. 21, 329–340 (2020).

Article 
CAS 
PubMed 

Google Scholar 

Huang, J. et al. Association between plant and animal protein intake and overall and cause-specific mortality. JAMA Intern. Med. 180, 1173–1184 (2020).

Article 
CAS 
PubMed 

Google Scholar 

Green, C. L. et al. Sex and genetic background define the metabolic, physiologic, and molecular response to protein restriction. Cell Metab. 34, 209–226 (2022).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Condon, K. J. & Sabatini, D. M. Nutrient regulation of mTORC1 at a glance. J. Cell Sci. 132, 0–2 (2019).

Article 
CAS 

Google Scholar 

Bar-Peled, L. et al. A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340, 1100–1106 (2013).

Article 
ADS 
CAS 
PubMed 
PubMed Central 

Google Scholar 

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).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Han, J. M. et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424 (2012).

Article 
CAS 
PubMed 

Google Scholar 

Wyant, G. A. et al. mTORC1 activator SLC38A9 is required to efflux essential amino acids from lysosomes and use protein as a nutrient. Cell 171, 642–654 (2017).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Son, S. M. et al. Leucine signals to mTORC1 via its metabolite acetyl-Coenzyme A. Cell Metab. 29, 192–201 (2019).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Yoshida, S., Pacitto, R., Yao, Y., Inoki, K. & Swanson, J. A. Growth factor signaling to mTORC1 by amino acid-laden macropinosomes. J. Cell Biol. 211, 159–172 (2015).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Doodnauth, S. A., Grinstein, S. & Maxson, M. E. Constitutive and stimulated macropinocytosis in macrophages: roles in immunity and in the pathogenesis of atherosclerosis. Philos. Trans. R Soc. B Biol. Sci. 374, 20180147 (2019).

Article 
CAS 

Google Scholar 

Lynch, C. J., Fox, H. L., Vary, T. C., Jefferson, L. S. & Kimball, S. R. Regulation of amino acid-sensitive TOR signaling by leucine analogues in adipocytes. J. Cell. Biochem. 77, 234–251 (2000).

Article 
CAS 
PubMed 

Google Scholar 

Treviño-Villarreal, J. H. et al. Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms. JCI Insight. 3, e99470 (2018).

Article 
PubMed 
PubMed Central 

Google Scholar 

Maida, A. et al. Dietary protein dilution limits dyslipidemia in obesity through FGF21-driven fatty acid clearance. J. Nutr. Biochem. 57, 189–196 (2018).

Article 
CAS 
PubMed 

Google Scholar 

Smith, G. I. et al. High-protein intake during weight loss therapy eliminates the weight-loss-induced improvement in insulin action in obese postmenopausal women. Cell Rep. 17, 849–861 (2016).

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

van Vliet, S. et al. The muscle anabolic effect of protein ingestion during a hyperinsulinaemic euglycaemic clamp in middle-aged women is not caused by leucine alone. J. Physiol. 596, 4681–4692 (2018).

Article 
PubMed 
PubMed Central 

Google Scholar 

Dietzen, D. J. et al. Rapid comprehensive amino acid analysis by liquid chromatography/tandem mass spectrometry: comparison to cation exchange with post-column ninhydrin detection. Rapid Commun. Mass Spectrom. 22, 3481–3488 (2008).

Article 
CAS 
PubMed 

Google Scholar 

You May Also Like

More From Author

+ There are no comments

Add yours