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Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the \u03b2-hydroxybutyrate (\u03b2HB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-\u03b2HB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the \u03b2HB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the \u03b2HB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation.<\/jats:p>","DOI":"10.1038\/s41598-024-62723-7","type":"journal-article","created":{"date-parts":[[2024,5,24]],"date-time":"2024-05-24T20:20:58Z","timestamp":1716582058000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy"],"prefix":"10.1038","volume":"14","author":[{"given":"Hester","family":"Meeusen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Romagnolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie A. 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Martin","family":"Verkuyl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose P.","family":"Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,5,24]]},"reference":[{"key":"62723_CR1","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1152\/physrev.1980.60.1.143","volume":"60","author":"AM Robinson","year":"1980","unstructured":"Robinson, A. M. & Williamson, D. H. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol. Rev. 60, 143\u2013187. https:\/\/doi.org\/10.1152\/physrev.1980.60.1.143 (1980).","journal-title":"Physiol. 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