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In addition, ethical committees may require ad libitum feeding. However, feeding affects the metabolism so ad libitum feeding may mask the effects of drugs on tissues directly involved in the digestion process (e.g., jejunum and liver). Despite this effect, principal component analysis has the potential of identifying metabolic traits that are statistically independent (orthogonal) to ad libitum feeding. Consequently, we used principal component analysis to discover the metabolic effects of doxorubicin independent of ad libitum feeding. First, we analyzed the lipidome of the jejunum and the liver of rats treated with vehicle or doxorubicin. Subsequently, we performed principal component analysis. We could identify a principal component associated to the hydrolysis of lipids during digestion and a group of lipids that were orthogonal. These lipids in the jejunum increased with the treatment time and presented a polyunsaturated fatty acid as common structural trait. This characteristic suggests that doxorubicin increases polyunsaturated fatty acids. This behavior agrees with our previous in vitro results and suggests that doxorubicin sensitized the jejunum to ferroptosis, which may partially explain the toxicity of doxorubicin in the intestines.<\/jats:p>","DOI":"10.3390\/metabo12090866","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T23:16:36Z","timestamp":1663197396000},"page":"866","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Orthogonality in Principal Component Analysis Allows the Discovery of Lipids in the Jejunum That Are Independent of Ad Libitum Feeding"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6463-4502","authenticated-orcid":false,"given":"David","family":"Balgoma","sequence":"first","affiliation":[{"name":"Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden"},{"name":"Unidad de Excelencia, Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (IBGM), Universidad de Valladolid\u2014Consejo Superior de Investigaciones Cient\u00edficas (CSIC), 47003 Valladolid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3764-4198","authenticated-orcid":false,"given":"Fredrik","family":"Kullenberg","sequence":"additional","affiliation":[{"name":"Translational Drug Development and Discovery, Department of Pharmaceutical Biosciences, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1384-2103","authenticated-orcid":false,"given":"Karsten","family":"Peters","sequence":"additional","affiliation":[{"name":"Translational Drug Development and Discovery, Department of Pharmaceutical Biosciences, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5586-2906","authenticated-orcid":false,"given":"David","family":"Dahlgren","sequence":"additional","affiliation":[{"name":"Translational Drug Development and Discovery, Department of Pharmaceutical Biosciences, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1987-7676","authenticated-orcid":false,"given":"Femke","family":"Heindryckx","sequence":"additional","affiliation":[{"name":"Department of Medical Cell Biology, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1578-5184","authenticated-orcid":false,"given":"Hans","family":"Lennern\u00e4s","sequence":"additional","affiliation":[{"name":"Translational Drug Development and Discovery, Department of Pharmaceutical Biosciences, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8962-2815","authenticated-orcid":false,"given":"Mikael","family":"Hedeland","sequence":"additional","affiliation":[{"name":"Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, 751 23 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0163-7827(03)00050-X","article-title":"The Digestion of Dietary Triacylglycerols","volume":"43","author":"Mu","year":"2004","journal-title":"Prog. Lipid Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.aca.2019.01.017","article-title":"Modeling the Fragmentation Patterns of Triacylglycerides in Mass Spectrometry Allows the Quantification of the Regioisomers with a Minimal Number of Standards","volume":"1057","author":"Balgoma","year":"2019","journal-title":"Anal. Chim. Acta"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"G425","DOI":"10.1152\/ajpgi.00320.2018","article-title":"Pancreatic and Mucosal Enzymes in Choline Phospholipid Digestion","volume":"316","author":"Nilsson","year":"2019","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"James, G., Witten, D., Hastie, T., and Tibshirani, R. (2013). An Introduction to Statistical Learning: With Applications in R, Springer. Springer Texts in Statistics.","DOI":"10.1007\/978-1-4614-7138-7"},{"key":"ref_5","unstructured":"Shlens, J. (2014). A Tutorial on Principal Component Analysis. arXiv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104304","DOI":"10.1016\/j.chemolab.2021.104304","article-title":"Efficient Tools for Principal Component Analysis of Complex Data\u2014A Tutorial","volume":"213","author":"Rodionova","year":"2021","journal-title":"Chemom. Intell. Lab. Syst."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Balgoma, D., Kullenberg, F., Calitz, C., Kopsida, M., Heindryckx, F., Lennern\u00e4s, H., and Hedeland, M. (2021). Anthracyclins Increase PUFAs: Potential Implications in ER Stress and Cell Death. 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Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1007\/s11306-019-1632-0","article-title":"Anabolic Androgenic Steroids Exert a Selective Remodeling of the Plasma Lipidome That Mirrors the Decrease of the de Novo Lipogenesis in the Liver","volume":"16","author":"Balgoma","year":"2020","journal-title":"Metabolomics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/mas.10061","article-title":"Electrospray Mass Spectrometry of Phospholipids","volume":"22","author":"Pulfer","year":"2003","journal-title":"Mass Spectrom. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1016\/j.jasms.2005.04.017","article-title":"Direct Qualitative Analysis of Triacylglycerols by Electrospray Mass Spectrometry Using a Linear Ion Trap","volume":"16","author":"McAnoy","year":"2005","journal-title":"J. Am. Soc. 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Stat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1136\/bmj.292.6522.746","article-title":"Confidence Intervals Rather than P Values: Estimation Rather than Hypothesis Testing","volume":"292","author":"Gardner","year":"1986","journal-title":"Br. Med. J. Clin. Res. 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