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It is currently unclear if carnitine deficiency and\/or acylcarnitine accumulation play a role in the pathophysiology of FAO disorders. The long\u2010chain acyl\u2010CoA dehydrogenase (LCAD) KO mouse is a model for long\u2010chain FAO disorders and is characterised by decreased levels of tissue and plasma free carnitine. Tissue levels of carnitine are controlled by SLC22A5, the plasmalemmal carnitine transporter. Here, we have further decreased carnitine availability in the LCAD KO mouse through a genetic intervention by introducing one defective <jats:italic>Slc22a5<\/jats:italic> allele (<jats:italic>jvs)<\/jats:italic>. <jats:italic>Slc22a5<\/jats:italic> haploinsufficiency decreased free carnitine levels in liver, kidney, and heart of LCAD KO animals. The resulting decrease in the tissue long\u2010chain acylcarnitines levels had a similar magnitude as the decrease in free carnitine. Levels of cardiac deoxycarnitine, a carnitine biosynthesis intermediate, were elevated due to <jats:italic>Slc22a5<\/jats:italic> haploinsufficiency in LCAD KO mice. A similar increase in heart and muscle deoxycarnitine was observed in an independent experiment using <jats:italic>Slc22a5<\/jats:italic><jats:sup>jvs\/jvs<\/jats:sup> mice. Cardiac hypertrophy, fasting\u2010induced hypoglycemia and increased liver weight, the major phenotypes of the LCAD KO mouse, were not affected by <jats:italic>Slc22a5<\/jats:italic> haploinsufficiency. This may suggest that secondary carnitine deficiency does not play a major role in the pathophysiology of these phenotypes. Similarly, our data do not support a major role for toxicity of long\u2010chain acylcarnitines in the phenotype of the LCAD KO mouse.<\/jats:p>","DOI":"10.1002\/jimd.12204","type":"journal-article","created":{"date-parts":[[2019,12,17]],"date-time":"2019-12-17T09:38:12Z","timestamp":1576575492000},"page":"486-495","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<i>Slc22a5<\/i> haploinsufficiency does not aggravate the phenotype of the long\u2010chain acyl\u2010CoA dehydrogenase KO mouse"],"prefix":"10.1002","volume":"43","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6478-3815","authenticated-orcid":false,"given":"Pablo","family":"Ranea\u2010Robles","sequence":"first","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunli","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai  New York New York"},{"name":"Mount Sinai Genomics, Inc.  New York New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"van Vlies","sequence":"additional","affiliation":[{"name":"Institute for Translational Vaccinology  Bilthoven The Netherlands"},{"name":"Department of Clinical Chemistry, Amsterdam Gastroenterology &amp; Metabolism Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fr\u00e9d\u00e9ric M.","family":"Vaz","sequence":"additional","affiliation":[{"name":"Department of Clinical Chemistry, Amsterdam Gastroenterology &amp; Metabolism Laboratory Genetic Metabolic Diseases, Amsterdam UMC, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6167-9147","authenticated-orcid":false,"given":"Sander M.","family":"Houten","sequence":"additional","affiliation":[{"name":"Department of Genetics 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