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Using a combination of pharmacological inhibition and clustered regularly interspaced short palindromic repeats (CRISPR)\u2010CRISPR associated protein 9 genome editing technology to simultaneously manipulate peroxisomal and mitochondrial fatty acid \u03b2\u2010oxidation (FAO) in HEK\u2010293 cells, we identified essential players in the metabolic crosstalk between these organelles. Depletion of carnitine palmitoyltransferase (CPT)2 activity through pharmacological inhibition or knockout (KO) uncovered a significant residual peroxisomal oxidation of lauric and palmitic acid, leading to the production of peroxisomal acylcarnitine intermediates. Generation and analysis of additional single\u2010 and double\u2010KO cell lines revealed that the D\u2010bifunctional protein (HSD17B4) and the peroxisomal ABC transporter ABCD3 are essential in peroxisomal oxidation of lauric and palmitic acid. Our results indicate that peroxisomes not only accept acyl\u2010CoAs but can also oxidize acylcarnitines in a similar biochemical pathway. By using an\n                    <jats:italic>Hsd17b4<\/jats:italic>\n                    KO mouse model, we demonstrated that peroxisomes contribute to the plasma acylcarnitine profile after acute inhibition of CPT2, proving\n                    <jats:italic>in vivo<\/jats:italic>\n                    relevance of this pathway. We summarize that peroxisomal FAO is important when mitochondrial FAO is defective or overloaded.\u2014Violante, S., Achetib, N., van Roermund, C. W. T., Hagen, J., Dodatko, T., Vaz, F. M., Waterham, H. R., Chen, H., Baes, M., Yu, C., Argmann, C. A., Houten, S. M. Peroxisomes can oxidize medium\u2010 and long\u2010chain fatty acids through a pathway involving ABCD3 and HSD17B4. FASEB J. 33, 4355\u20134364 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201801498r","type":"journal-article","created":{"date-parts":[[2018,12,12]],"date-time":"2018-12-12T16:59:11Z","timestamp":1544633951000},"page":"4355-4364","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["Peroxisomes can oxidize medium\u2010 and long\u2010chain fatty acids through a pathway involving ABCD3 and HSD17B4"],"prefix":"10.1096","volume":"33","author":[{"given":"Sara","family":"Violante","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Icahn Institute for Data Science and Genomic Technology Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Mount Sinai Genomics, Incorporated  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihad","family":"Achetib","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai  New York New York USA"},{"name":"Icahn Institute for Data Science and Genomic Technology Icahn School of Medicine at Mount Sinai  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo W. 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