{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:31:19Z","timestamp":1791217879885,"version":"4.1.0"},"reference-count":133,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,20]],"date-time":"2019-07-20T00:00:00Z","timestamp":1563580800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research","award":["18K08232, 15KT0088, 16K15465, 18H02727"],"award-info":[{"award-number":["18K08232, 15KT0088, 16K15465, 18H02727"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Dyslipidemia is a common nutritional and metabolic disorder in patients with chronic kidney disease. Accumulating evidence supports the hypothesis that prolonged metabolic imbalance of lipids leads to ectopic fat distribution in the peripheral organs (lipotoxicity), including the kidney, heart, and skeletal muscle, which accelerates peripheral inflammation and afflictions. Thus, lipotoxicity may partly explain progression of renal dysfunction and even extrarenal complications, including renal anemia, heart failure, and sarcopenia. Additionally, endoplasmic reticulum stress activated by the unfolded protein response pathway plays a pivotal role in lipotoxicity by modulating the expression of key enzymes in lipid synthesis and oxidation. Here, we review the molecular mechanisms underlying lipid deposition and resultant tissue damage in the kidney, heart, and skeletal muscle, with the goal of illuminating the nutritional aspects of these pathologies.<\/jats:p>","DOI":"10.3390\/nu11071664","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T02:55:37Z","timestamp":1563764137000},"page":"1664","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":162,"title":["Lipotoxicity in Kidney, Heart, and Skeletal Muscle Dysfunction"],"prefix":"10.3390","volume":"11","author":[{"given":"Hiroshi","family":"Nishi","sequence":"first","affiliation":[{"name":"Division of Nephrology and Endocrinology, the University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takaaki","family":"Higashihara","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Endocrinology, the University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7032-7736","authenticated-orcid":false,"given":"Reiko","family":"Inagi","sequence":"additional","affiliation":[{"name":"Division of CKD Pathophysiology, the University of Tokyo Graduate School of Medicine, Tokyo 113-8655, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2414","DOI":"10.1001\/jama.287.18.2414","article-title":"The glycemic index: Physiological mechanisms relating to obesity, diabetes, and cardiovascular disease","volume":"287","author":"Ludwig","year":"2002","journal-title":"JAMA"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1210\/er.2017-00111","article-title":"Obesity Pathogenesis: An Endocrine Society Scientific Statement","volume":"38","author":"Schwartz","year":"2017","journal-title":"Endocr. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/ejcn.2016.230","article-title":"Impact of dietary glycemic challenge on fuel partitioning","volume":"71","author":"Hagele","year":"2017","journal-title":"Eur. J. Clin. Nutr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"k4583","DOI":"10.1136\/bmj.k4583","article-title":"Effects of a low carbohydrate diet on energy expenditure during weight loss maintenance: Randomized trial","volume":"363","author":"Ebbeling","year":"2018","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1126\/science.aau2096","article-title":"Dietary fat: From foe to friend?","volume":"362","author":"Ludwig","year":"2018","journal-title":"Science"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.bbalip.2009.09.007","article-title":"The role of dietary protein on lipotoxicity","volume":"1801","author":"Tovar","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.atherosclerosis.2008.06.019","article-title":"Nutritional and nutraceutical approaches to dyslipidemia and atherosclerosis prevention: Focus on dietary proteins","volume":"203","author":"Sirtori","year":"2009","journal-title":"Atherosclerosis"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/1476-511X-10-85","article-title":"Screening of soy protein-derived hypotriglyceridemic di-peptides in vitro and in vivo","volume":"10","author":"Inoue","year":"2011","journal-title":"Lipids Health Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1016\/j.jnutbio.2015.03.008","article-title":"Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome","volume":"26","author":"Parafati","year":"2015","journal-title":"J. Nutr. Biochem."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Parafati, M., Lascala, A., La Russa, D., Mignogna, C., Trimboli, F., Morittu, V.M., Riillo, C., Macirella, R., Mollace, V., and Brunelli, E. (2018). Bergamot Polyphenols Boost Therapeutic Effects of the Diet on Non-Alcoholic Steatohepatitis (NASH) Induced by \"Junk Food\": Evidence for Anti-Inflammatory Activity. Nutrients, 10.","DOI":"10.3390\/nu10111604"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1053\/j.gastro.2018.06.031","article-title":"Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis","volume":"155","author":"Musso","year":"2018","journal-title":"Gastroenterology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1097\/MCO.0b013e32832182ee","article-title":"Saturated with fat: New perspectives on lipotoxicity","volume":"12","author":"Garbarino","year":"2009","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.ijcard.2013.08.077","article-title":"Ectopic fat and cardiometabolic and vascular risk","volume":"169","author":"Lim","year":"2013","journal-title":"Int J. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1159\/000144024","article-title":"Dyslipidemia in chronic kidney disease: An approach to pathogenesis and treatment","volume":"28","author":"Tsimihodimos","year":"2008","journal-title":"Am. J. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1159\/000337821","article-title":"Lipid disorders in uremia and dialysis","volume":"178","author":"Bakris","year":"2012","journal-title":"Contrib. Nephrol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S118","DOI":"10.2337\/diabetes.50.2007.S118","article-title":"Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover","volume":"50","author":"Unger","year":"2001","journal-title":"Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.bbalip.2009.10.006","article-title":"Lipid homeostasis, lipotoxicity and the metabolic syndrome","volume":"1801","author":"Unger","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1681\/ASN.2005111241","article-title":"Increasing body mass index and obesity in the incident ESRD population","volume":"17","author":"Kramer","year":"2006","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"251","DOI":"10.7326\/0003-4819-157-4-201208210-00005","article-title":"Lipid-lowering therapy in persons with chronic kidney disease: A systematic review and meta-analysis","volume":"157","author":"Upadhyay","year":"2012","journal-title":"Ann. Intern. Med."},{"key":"ref_20","first-page":"E650","article-title":"Human kidney free fatty acid and glucose uptake: Evidence for a renal glucose-fatty acid cycle","volume":"273","author":"Meyer","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/S0140-6736(68)90589-8","article-title":"Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis","volume":"2","author":"Risdon","year":"1968","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/S0140-6736(77)90362-2","article-title":"Close genetic linkage between HLA and congenital adrenal hyperplasia (21-hydroxylase deficiency)","volume":"2","author":"Dupont","year":"1977","journal-title":"Lancet"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1560","DOI":"10.1038\/sj.ki.5001834","article-title":"Lipotoxicity","volume":"70","author":"Weinberg","year":"2006","journal-title":"Kidney Int."},{"key":"ref_24","first-page":"813","article-title":"Fas-dependent fratricidal apoptosis is a mechanism of tubular epithelial cell deletion in chronic renal failure","volume":"78","author":"Schelling","year":"1998","journal-title":"Lab. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1093\/ndt\/gfh964","article-title":"Addition of oleic acid to delipidated bovine serum albumin aggravates renal damage in experimental protein-overload nephrosis","volume":"20","author":"Bakker","year":"2005","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1628","DOI":"10.1046\/j.1523-1755.2002.00618.x","article-title":"Urinary free fatty acids bound to albumin aggravate tubulointerstitial damage","volume":"62","author":"Kamijo","year":"2002","journal-title":"Kidney Int."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1172\/JCI71863","article-title":"Lipotoxic disruption of NHE1 interaction with PI(4,5)P2 expedites proximal tubule apoptosis","volume":"124","author":"Khan","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"F896","DOI":"10.1152\/ajprenal.00484.2013","article-title":"Albumin-bound fatty acids but not albumin itself alter redox balance in tubular epithelial cells and induce a peroxide-mediated redox-sensitive apoptosis","volume":"306","author":"Ruggiero","year":"2014","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Susztak, K., Ciccone, E., McCue, P., Sharma, K., and Bottinger, E.P. (2005). Multiple metabolic hits converge on CD36 as novel mediator of tubular epithelial apoptosis in diabetic nephropathy. PLoS Med., 2.","DOI":"10.1371\/journal.pmed.0020045"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nm.3762","article-title":"Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development","volume":"21","author":"Kang","year":"2015","journal-title":"Nat. Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1681\/ASN.2017030314","article-title":"Kidney Proximal Tubule Lipoapoptosis Is Regulated by Fatty Acid Transporter-2 (FATP2)","volume":"29","author":"Khan","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2074","DOI":"10.2337\/db11-1437","article-title":"Oxidation of fatty acids is the source of increased mitochondrial reactive oxygen species production in kidney cortical tubules in early diabetes","volume":"61","author":"Rosca","year":"2012","journal-title":"Diabetes"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"La Russa, D., Giordano, F., Marrone, A., Parafati, M., Janda, E., and Pellegrino, D. (2019). Oxidative Imbalance and Kidney Damage in Cafeteria Diet-Induced Rat Model of Metabolic Syndrome: Effect of Bergamot Polyphenolic Fraction. Antioxidants (Basel), 8.","DOI":"10.3390\/antiox8030066"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"18919","DOI":"10.1074\/jbc.M110650200","article-title":"Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus","volume":"277","author":"Sun","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.2337\/db05-0603","article-title":"Regulation of renal fatty acid and cholesterol metabolism, inflammation, and fibrosis in Akita and OVE26 mice with type 1 diabetes","volume":"55","author":"Proctor","year":"2006","journal-title":"Diabetes"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1038\/sj.ki.5001704","article-title":"Albumin induces endoplasmic reticulum stress and apoptosis in renal proximal tubular cells","volume":"70","author":"Ohse","year":"2006","journal-title":"Kidney Int."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"F568","DOI":"10.1152\/ajprenal.00659.2009","article-title":"Indoxyl sulfate inhibits proliferation of human proximal tubular cells via endoplasmic reticulum stress","volume":"299","author":"Kawakami","year":"2010","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"74","DOI":"10.3389\/fphys.2017.00074","article-title":"Stress Signal Network between Hypoxia and ER Stress in Chronic Kidney Disease","volume":"8","author":"Maekawa","year":"2017","journal-title":"Front. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Inoue, T., Maekawa, H., and Inagi, R. (2019). Organelle crosstalk in the kidney. Kidney Int.","DOI":"10.1016\/j.kint.2018.11.035"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.kint.2018.09.023","article-title":"ATF6alpha downregulation of PPARalpha promotes lipotoxicity-induced tubulointerstitial fibrosis","volume":"95","author":"Jao","year":"2019","journal-title":"Kidney Int."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1016\/j.freeradbiomed.2010.03.021","article-title":"Lipotoxicity in renal proximal tubular cells: Relationship between endoplasmic reticulum stress and oxidative stress pathways","volume":"48","author":"Katsoulieris","year":"2010","journal-title":"Free Radic. Biol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2225","DOI":"10.1681\/ASN.2007121313","article-title":"Proteinuria and hyperglycemia induce endoplasmic reticulum stress","volume":"19","author":"Lindenmeyer","year":"2008","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"967826","DOI":"10.1155\/2014\/967826","article-title":"Pathophysiology of cisplatin-induced acute kidney injury","volume":"2014","author":"Ozkok","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1904","DOI":"10.2337\/db15-1637","article-title":"Hepatic ATF6 Increases Fatty Acid Oxidation to Attenuate Hepatic Steatosis in Mice Through Peroxisome Proliferator-Activated Receptor alpha","volume":"65","author":"Chen","year":"2016","journal-title":"Diabetes"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1038\/ki.1991.49","article-title":"Anatomy of the renal interstitium","volume":"39","author":"Lemley","year":"1991","journal-title":"Kidney Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1681\/ASN.2011070680","article-title":"The renal mononuclear phagocytic system","volume":"23","author":"Nelson","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1831","DOI":"10.2215\/CJN.00640114","article-title":"Physiology of the Renal Interstitium","volume":"10","author":"Zeisberg","year":"2015","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1159\/000417877","article-title":"Site of erythropoietin formation","volume":"76","author":"Kurtz","year":"1989","journal-title":"Contrib. Nephrol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5223","DOI":"10.1182\/blood-2007-10-115857","article-title":"Repression via the GATA box is essential for tissue-specific erythropoietin gene expression","volume":"111","author":"Obara","year":"2008","journal-title":"Blood"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Pan, X., Suzuki, N., Hirano, I., Yamazaki, S., Minegishi, N., and Yamamoto, M. (2011). Isolation and characterization of renal erythropoietin-producing cells from genetically produced anemia mice. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0025839"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Anusornvongchai, T., Nangaku, M., Jao, T.M., Wu, C.H., Ishimoto, Y., Maekawa, H., Tanaka, T., Shimizu, A., Yamamoto, M., and Suzuki, N. (2018). Palmitate deranges erythropoietin production via transcription factor ATF4 activation of unfolded protein response. Kidney Int.","DOI":"10.1016\/j.kint.2018.03.011"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"7683","DOI":"10.1093\/nar\/gkt563","article-title":"The eIF2alpha\/ATF4 pathway is essential for stress-induced autophagy gene expression","volume":"41","author":"Maurin","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s00125-012-2747-2","article-title":"Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1alpha axis in db\/db mice","volume":"56","author":"Kim","year":"2013","journal-title":"Diabetologia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1016\/j.cmet.2016.04.011","article-title":"Adiponectin, Leptin, and Fatty Acids in the Maintenance of Metabolic Homeostasis through Adipose Tissue Crosstalk","volume":"23","author":"Stern","year":"2016","journal-title":"Cell Metab."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/j.kint.2016.06.013","article-title":"Protection of mitochondria prevents high-fat diet-induced glomerulopathy and proximal tubular injury","volume":"90","author":"Szeto","year":"2016","journal-title":"Kidney Int."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1016\/j.cmet.2017.01.004","article-title":"Reducing VEGF-B Signaling Ameliorates Renal Lipotoxicity and Protects against Diabetic Kidney Disease","volume":"25","author":"Falkevall","year":"2017","journal-title":"Cell Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1681\/ASN.2011060627","article-title":"Circulating TNF receptors 1 and 2 predict ESRD in type 2 diabetes","volume":"23","author":"Niewczas","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1681\/ASN.2011060628","article-title":"Circulating TNF receptors 1 and 2 predict stage 3 CKD in type 1 diabetes","volume":"23","author":"Gohda","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3336","DOI":"10.1172\/JCI85939","article-title":"Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury","volume":"126","author":"Pedigo","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3209","DOI":"10.1002\/jcp.25867","article-title":"Palmitate induces mitochondrial superoxide generation and activates AMPK in podocytes","volume":"232","author":"Lee","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9060","DOI":"10.1002\/jcp.26875","article-title":"Peroxidase expression is decreased by palmitate in cultured podocytes but increased in podocytes of advanced diabetic nephropathy","volume":"233","author":"Lee","year":"2018","journal-title":"J. Cell Physiol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.metabol.2018.02.004","article-title":"Adiponectin receptor agonist AdipoRon decreased ceramide, and lipotoxicity, and ameliorated diabetic nephropathy","volume":"85","author":"Choi","year":"2018","journal-title":"Metabolism"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1108","DOI":"10.1681\/ASN.2017060627","article-title":"The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes","volume":"29","author":"Kim","year":"2018","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1053\/j.arrt.2004.04.011","article-title":"The evaluation of underlying cardiovascular disease among patients with end-stage renal disease","volume":"11","author":"Hedayati","year":"2004","journal-title":"Adv. Chronic Kidney Dis."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1111\/j.1440-1797.2010.01266.x","article-title":"Left ventricular geometry and cardiovascular mortality based on haemodialysis patient autopsy analyses","volume":"15","author":"Mimura","year":"2010","journal-title":"Nephrology (Carlton)"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1161\/CIRCULATIONAHA.118.034588","article-title":"Uremic Toxin Indoxyl Sulfate Promotes Proinflammatory Macrophage Activation Via the Interplay of OATP2B1 and Dll4-Notch Signaling","volume":"139","author":"Nakano","year":"2019","journal-title":"Circulation"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1887","DOI":"10.1046\/j.1523-1755.2002.00324.x","article-title":"Hypocholesterolemia is a significant predictor of death in a cohort of chronic hemodialysis patients","volume":"61","author":"Iseki","year":"2002","journal-title":"Kidney Int."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"8567275","DOI":"10.1155\/2019\/8567275","article-title":"Oxidative Balance and Inflammation in Hemodialysis Patients: Biomarkers of Cardiovascular Risk?","volume":"2019","author":"Russa","year":"2019","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1152\/physrev.00006.2004","article-title":"Myocardial substrate metabolism in the normal and failing heart","volume":"85","author":"Stanley","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.1096\/fj.201700300R","article-title":"Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes","volume":"32","author":"Law","year":"2018","journal-title":"FASEB J."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1161\/01.ATV.0000030199.06252.26","article-title":"Microsomal triglyceride transfer protein gene expression and triglyceride accumulation in hypoxic human hearts","volume":"22","author":"Nielsen","year":"2002","journal-title":"Arterioscler. Thromb Vasc. Biol"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1161\/01.CIR.0000137836.95625.D4","article-title":"Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: Possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis","volume":"110","author":"Okada","year":"2004","journal-title":"Circulation"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"H1411","DOI":"10.1152\/ajpheart.01378.2005","article-title":"Activation of endoplasmic reticulum stress response during the development of ischemic heart disease","volume":"291","author":"Azfer","year":"2006","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2625","DOI":"10.1172\/JCI43068","article-title":"The VLDL receptor promotes lipotoxicity and increases mortality in mice following an acute myocardial infarction","volume":"121","author":"Perman","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Drevinge, C., Karlsson, L.O., Stahlman, M., Larsson, T., Perman Sundelin, J., Grip, L., Andersson, L., Boren, J., and Levin, M.C. (2013). Cholesteryl esters accumulate in the heart in a porcine model of ischemia and reperfusion. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0061942"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.ijcard.2014.03.176","article-title":"PPARbeta\/delta attenuates palmitate-induced endoplasmic reticulum stress and induces autophagic markers in human cardiac cells","volume":"174","author":"Palomer","year":"2014","journal-title":"Int. J. Cardiol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1016\/j.bbalip.2014.09.012","article-title":"Sequestration of fatty acids in triglycerides prevents endoplasmic reticulum stress in an in vitro model of cardiomyocyte lipotoxicity","volume":"1841","author":"Bosma","year":"2014","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6934","DOI":"10.3892\/mmr.2017.7404","article-title":"Palmitate induces myocardial lipotoxic injury via the endoplasmic reticulum stressmediated apoptosis pathway","volume":"16","author":"Zou","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1073\/pnas.97.4.1784","article-title":"Lipotoxic heart disease in obese rats: Implications for human obesity","volume":"97","author":"Zhou","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1161\/CIRCRESAHA.117.311307","article-title":"Mitochondrial Reactive Oxygen Species in Lipotoxic Hearts Induce Post-Translational Modifications of AKAP121, DRP1, and OPA1 That Promote Mitochondrial Fission","volume":"122","author":"Tsushima","year":"2018","journal-title":"Circ. Res."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Medina-Gomez, G., Gray, S.L., Yetukuri, L., Shimomura, K., Virtue, S., Campbell, M., Curtis, R.K., Jimenez-Linan, M., Blount, M., and Yeo, G.S. (2007). PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. PLoS Genet., 3.","DOI":"10.1371\/journal.pgen.0030064"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.febslet.2012.11.019","article-title":"Doxorubicin treatment inhibits PPARgamma and may induce lipotoxicity by mimicking a type 2 diabetes-like condition in rodent models","volume":"587","author":"Arunachalam","year":"2013","journal-title":"FEBS Lett."},{"key":"ref_83","first-page":"E769","article-title":"Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans","volume":"255","author":"Baron","year":"1988","journal-title":"Am. J. Physiol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"E1315","DOI":"10.1152\/ajpendo.00561.2011","article-title":"Lipid metabolism in skeletal muscle: Generation of adaptive and maladaptive intracellular signals for cellular function","volume":"302","author":"Watt","year":"2012","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1007\/s41048-015-0013-0","article-title":"Skeletal intramyocellular lipid metabolism and insulin resistance","volume":"1","author":"Li","year":"2015","journal-title":"Biophys. Rep."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2099","DOI":"10.1194\/jlr.R066514","article-title":"Lipid signaling and lipotoxicity in metaflammation: Indications for metabolic disease pathogenesis and treatment","volume":"57","author":"Ertunc","year":"2016","journal-title":"J. Lipid. Res."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"E1009","DOI":"10.1152\/ajpendo.90558.2008","article-title":"Metabolic flexibility and insulin resistance","volume":"295","author":"Galgani","year":"2008","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"E741","DOI":"10.1152\/ajpendo.00514.2002","article-title":"Skeletal muscle lipid metabolism with obesity","volume":"284","author":"Hulver","year":"2003","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"11107","DOI":"10.1074\/jbc.M708700200","article-title":"Oleate reverses palmitate-induced insulin resistance and inflammation in skeletal muscle cells","volume":"283","author":"Coll","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"E1341","DOI":"10.1152\/ajpendo.00095.2006","article-title":"Apoptosis in skeletal muscle myotubes is induced by ceramides and is positively related to insulin resistance","volume":"291","author":"Turpin","year":"2006","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.2337\/diabetes.48.8.1572","article-title":"Glucose turnover and adipose tissue lipolysis are insulin-resistant in healthy relatives of type 2 diabetes patients: Is cellular insulin resistance a secondary phenomenon?","volume":"48","author":"Eriksson","year":"1999","journal-title":"Diabetes"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1038\/nature06902","article-title":"Dynamics of fat cell turnover in humans","volume":"453","author":"Spalding","year":"2008","journal-title":"Nature"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.2337\/diabetes.51.7.2005","article-title":"Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha","volume":"51","author":"Itani","year":"2002","journal-title":"Diabetes"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1007\/s00125-011-2419-7","article-title":"Localisation and composition of skeletal muscle diacylglycerol predicts insulin resistance in humans","volume":"55","author":"Bergman","year":"2012","journal-title":"Diabetologia"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1210\/jc.2009-0053","article-title":"Influence of gender, obesity, and muscle lipase activity on intramyocellular lipids in sedentary individuals","volume":"94","author":"Moro","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.1007\/s00125-007-0781-2","article-title":"Increased skeletal muscle ceramide level in men at risk of developing type 2 diabetes","volume":"50","author":"Straczkowski","year":"2007","journal-title":"Diabetologia"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"80","DOI":"10.2337\/db09-0988","article-title":"Insulin resistance is associated with higher intramyocellular triglycerides in type I but not type II myocytes concomitant with higher ceramide content","volume":"59","author":"Coen","year":"2010","journal-title":"Diabetes"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1210\/jc.2011-1884","article-title":"Long- and medium-chain fatty acids induce insulin resistance to a similar extent in humans despite marked differences in muscle fat accumulation","volume":"97","author":"Hoeks","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"2372741","DOI":"10.1155\/2016\/2372741","article-title":"Training Does Not Alter Muscle Ceramide and Diacylglycerol in Offsprings of Type 2 Diabetic Patients Despite Improved Insulin Sensitivity","volume":"2016","author":"Sogaard","year":"2016","journal-title":"J. Diabetes Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5755","DOI":"10.1210\/jcem.86.12.8075","article-title":"Skeletal muscle lipid content and insulin resistance: Evidence for a paradox in endurance-trained athletes","volume":"86","author":"Goodpaster","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1152\/japplphysiol.00368.2004","article-title":"Use of intramuscular triacylglycerol as a substrate source during exercise in humans","volume":"97","year":"2004","journal-title":"J. Appl. Physiol. (1985)"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"C116","DOI":"10.1152\/ajpcell.00267.2007","article-title":"Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells","volume":"296","author":"Irrcher","year":"2009","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1139\/H07-062","article-title":"Mechanisms of calcium-induced mitochondrial biogenesis and GLUT4 synthesis","volume":"32","author":"Wright","year":"2007","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"12017","DOI":"10.1073\/pnas.0705070104","article-title":"AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha","volume":"104","author":"Jager","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1073\/pnas.0510452103","article-title":"Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency","volume":"103","author":"Hunt","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_106","first-page":"296","article-title":"Therapeutic actions of the Chinese herbal formulae with cold and heat properties and their effects on ultrastructures of synoviocytes in rats of the collagen-induced arthritis","volume":"22","author":"Li","year":"2002","journal-title":"J. Tradit. Chin. Med."},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Tadaishi, M., Miura, S., Kai, Y., Kano, Y., Oishi, Y., and Ezaki, O. (2011). Skeletal muscle-specific expression of PGC-1alpha-b, an exercise-responsive isoform, increases exercise capacity and peak oxygen uptake. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028290"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"E3300","DOI":"10.1073\/pnas.1418560112","article-title":"Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism","volume":"112","author":"Wicks","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.2337\/db10-0308","article-title":"Tauroursodeoxycholic Acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women","volume":"59","author":"Kars","year":"2010","journal-title":"Diabetes"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1553","DOI":"10.1007\/s00421-010-1783-1","article-title":"The unfolded protein response in human skeletal muscle is not involved in the onset of glucose tolerance impairment induced by a fat-rich diet","volume":"111","author":"Deldicque","year":"2011","journal-title":"Eur. J. Appl. Physiol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1007\/s00125-011-2328-9","article-title":"Endoplasmic reticulum stress does not mediate palmitate-induced insulin resistance in mouse and human muscle cells","volume":"55","author":"Hainault","year":"2012","journal-title":"Diabetologia"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/j.bbrc.2011.11.135","article-title":"Reduction of endoplasmic reticulum stress using chemical chaperones or Grp78 overexpression does not protect muscle cells from palmitate-induced insulin resistance","volume":"417","author":"Rieusset","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.2337\/db09-0188","article-title":"Individual stearoyl-coa desaturase 1 expression modulates endoplasmic reticulum stress and inflammation in human myotubes and is associated with skeletal muscle lipid storage and insulin sensitivity in vivo","volume":"58","author":"Peter","year":"2009","journal-title":"Diabetes"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"E695","DOI":"10.1152\/ajpendo.00038.2010","article-title":"The unfolded protein response is activated in skeletal muscle by high-fat feeding: Potential role in the downregulation of protein synthesis","volume":"299","author":"Deldicque","year":"2010","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"4757","DOI":"10.1021\/pr200553c","article-title":"Proteome of skeletal muscle lipid droplet reveals association with mitochondria and apolipoprotein a-I","volume":"10","author":"Zhang","year":"2011","journal-title":"J. Proteome. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1097\/MNH.0000000000000318","article-title":"Clinical relevance of sarcopenia in chronic kidney disease","volume":"26","author":"Moorthi","year":"2017","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.clnu.2013.04.002","article-title":"Prevalence of and factors associated with sarcopenia in elderly patients with end-stage renal disease","volume":"33","author":"Kim","year":"2014","journal-title":"Clin. Nutr."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"2079","DOI":"10.2215\/CJN.02140214","article-title":"Association of sarcopenia with eGFR and misclassification of obesity in adults with CKD in the United States","volume":"9","author":"Sharma","year":"2014","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1007\/s11255-014-0662-9","article-title":"Positive association of vigorous and moderate physical activity volumes with skeletal muscle mass but not bone density or metabolism markers in hemodialysis patients","volume":"46","author":"Morishita","year":"2014","journal-title":"Int. Urol. Nephrol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.ijcard.2018.03.064","article-title":"Non-invasive testing for sarcopenia predicts future cardiovascular events in patients with chronic kidney disease","volume":"268","author":"Hanatani","year":"2018","journal-title":"Int. J. Cardiol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1038\/ki.2009.524","article-title":"Both low muscle mass and low fat are associated with higher all-cause mortality in hemodialysis patients","volume":"77","author":"Huang","year":"2010","journal-title":"Kidney Int."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"32084","DOI":"10.1038\/srep32084","article-title":"Indoxyl sulfate potentiates skeletal muscle atrophy by inducing the oxidative stress-mediated expression of myostatin and atrogin-1","volume":"6","author":"Enoki","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"36618","DOI":"10.1038\/srep36618","article-title":"Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease","volume":"6","author":"Sato","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1002\/jcsm.12202","article-title":"Potential therapeutic interventions for chronic kidney disease-associated sarcopenia via indoxyl sulfate-induced mitochondrial dysfunction","volume":"8","author":"Enoki","year":"2017","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1002\/jcsm.12288","article-title":"The double-edged sword of endoplasmic reticulum stress in uremic sarcopenia through myogenesis perturbation","volume":"9","author":"Jheng","year":"2018","journal-title":"J. Cachexia Sarcopenia Muscle"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1093\/ajcn\/86.3.633","article-title":"Obese sarcopenia in patients with end-stage renal disease is associated with inflammation and increased mortality","volume":"86","author":"Honda","year":"2007","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1093\/ndt\/gft265","article-title":"Serum hepatocyte growth factor is associated with truncal fat mass and increased mortality in chronic kidney disease stage 5 patients with protein-energy wasting","volume":"30","author":"Yuan","year":"2015","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.3389\/fphys.2018.01648","article-title":"Mechanisms and Modulation of Oxidative\/Nitrative Stress in Type 4 Cardio-Renal Syndrome and Renal Sarcopenia","volume":"9","author":"Sarkozy","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_129","doi-asserted-by":"crossref","unstructured":"Sato, E., Saigusa, D., Mishima, E., Uchida, T., Miura, D., Morikawa-Ichinose, T., Kisu, K., Sekimoto, A., Saito, R., and Oe, Y. (2017). Impact of the Oral Adsorbent AST-120 on Organ-Specific Accumulation of Uremic Toxins: LC-MS\/MS and MS Imaging Techniques. Toxins (Basel), 10.","DOI":"10.3390\/toxins10010019"},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.cbi.2019.02.023","article-title":"Indoxyl sulfate induces myotube atrophy by ROS-ERK and JNK-MAFbx cascades","volume":"304","author":"Changchien","year":"2019","journal-title":"Chem. Biol. Interact."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"5159","DOI":"10.1096\/fj.201700126R","article-title":"Unacylated ghrelin normalizes skeletal muscle oxidative stress and prevents muscle catabolism by enhancing tissue mitophagy in experimental chronic kidney disease","volume":"31","author":"Semolic","year":"2017","journal-title":"FASEB J."},{"key":"ref_132","doi-asserted-by":"crossref","unstructured":"Wong, T.C., Chen, Y.T., Wu, P.Y., Chen, T.W., Chen, H.H., Chen, T.H., and Yang, S.H. (2015). Ratio of Dietary n-6\/n-3 Polyunsaturated Fatty Acids Independently Related to Muscle Mass Decline in Hemodialysis Patients. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0140402"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1056\/NEJMoa0810177","article-title":"Rosuvastatin and cardiovascular events in patients undergoing hemodialysis","volume":"360","author":"Fellstrom","year":"2009","journal-title":"N. Engl. J. Med."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/7\/1664\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:07:50Z","timestamp":1760188070000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/7\/1664"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,20]]},"references-count":133,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["nu11071664"],"URL":"https:\/\/doi.org\/10.3390\/nu11071664","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,20]]}}}