{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T13:52:53Z","timestamp":1756993973420,"version":"3.40.5"},"reference-count":19,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,6,22]],"date-time":"2023-06-22T00:00:00Z","timestamp":1687392000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000264","name":"Canadian Liver Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000264","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Basic Clin Pharma Tox"],"published-print":{"date-parts":[[2023,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Aims<\/jats:title><jats:p>Recent studies have demonstrated that stimulating pyruvate dehydrogenase (PDH, gene <jats:italic>Pdha1<\/jats:italic>), the rate\u2010limiting enzyme of glucose oxidation, can reverse obesity\u2010induced non\u2010alcoholic fatty liver disease (NAFLD), which can be achieved via treatment with the antianginal ranolazine. Accordingly, our aim was to determine whether ranolazine's ability to mitigate obesity\u2010induced NAFLD and hyperglycaemia requires increases in hepatic PDH activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We generated liver\u2010specific PDH\u2010deficient (<jats:italic>Pdha1<\/jats:italic><jats:sup>Liver\u2212\/\u2212<\/jats:sup>) mice, which were provided a high\u2010fat diet for 12\u2009weeks to induce obesity. <jats:italic>Pdha1<\/jats:italic><jats:sup>Liver\u2212\/\u2212<\/jats:sup> mice and their albumin\u2010Cre (Alb<jats:sup>Cre<\/jats:sup>) littermates were randomized to treatment with either vehicle control or ranolazine (50\u2009mg\/kg) once daily via oral gavage during the final 5\u00a0weeks, following which we assessed glucose and pyruvate tolerance.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p><jats:italic>Pdha1<\/jats:italic><jats:sup>Liver\u2212\/\u2212<\/jats:sup> mice exhibited no overt phenotypic differences (e.g. adiposity, glucose tolerance) when compared to their Alb<jats:sup>Cre<\/jats:sup> littermates. Of interest, ranolazine treatment improved glucose tolerance and mildly reduced hepatic triacylglycerol content in obese Alb<jats:sup>Cre<\/jats:sup> mice but not in obese <jats:italic>Pdha1<\/jats:italic><jats:sup>Liver\u2212\/\u2212<\/jats:sup> mice. The latter was independent of changes in hepatic mRNA expression of genes involved in regulating lipogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Liver\u2010specific PDH deficiency is insufficient to promote an NAFLD phenotype. Nonetheless, hepatic PDH activity partially contributes to how the antianginal ranolazine improves glucose tolerance and alleviates hepatic steatosis in obesity.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bcpt.13906","type":"journal-article","created":{"date-parts":[[2023,6,3]],"date-time":"2023-06-03T06:35:39Z","timestamp":1685774139000},"page":"194-201","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The antianginal ranolazine fails to improve glycaemia in obese liver\u2010specific pyruvate dehydrogenase deficient male mice"],"prefix":"10.1111","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4469-330X","authenticated-orcid":false,"given":"Christina T.","family":"Saed","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seyed Amirhossein","family":"Tabatabaei Dakhili","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda A.","family":"Greenwell","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordan S. F.","family":"Chan","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kunyan","family":"Yang","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keshav","family":"Gopal","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Farah","family":"Eaton","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rami","family":"Al Batran","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy Universit\u00e9 de Montr\u00e9al  Quebec Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9574-5707","authenticated-orcid":false,"given":"John R.","family":"Ussher","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton Alberta Canada"},{"name":"Alberta Diabetes Institute University of Alberta  Edmonton Alberta Canada"},{"name":"Cardiovascular Research Institute University of Alberta  Edmonton Alberta Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,6,22]]},"reference":[{"doi-asserted-by":"publisher","key":"e_1_2_7_2_1","DOI":"10.9778\/cmajo.20190212"},{"doi-asserted-by":"publisher","key":"e_1_2_7_3_1","DOI":"10.1016\/j.diabet.2016.04.002"},{"doi-asserted-by":"publisher","key":"e_1_2_7_4_1","DOI":"10.2337\/db16\u20100223"},{"doi-asserted-by":"publisher","key":"e_1_2_7_5_1","DOI":"10.1172\/jci.insight.124643"},{"doi-asserted-by":"publisher","key":"e_1_2_7_6_1","DOI":"10.1152\/jappl.1996.81.2.905"},{"doi-asserted-by":"publisher","key":"e_1_2_7_7_1","DOI":"10.1161\/01.CIR.93.1.135"},{"doi-asserted-by":"publisher","key":"e_1_2_7_8_1","DOI":"10.1111\/bcpt.13492"},{"doi-asserted-by":"publisher","key":"e_1_2_7_9_1","DOI":"10.1016\/j.cmet.2020.03.017"},{"doi-asserted-by":"publisher","key":"e_1_2_7_10_1","DOI":"10.1139\/cjpp\u20102021\u20100559"},{"doi-asserted-by":"publisher","key":"e_1_2_7_11_1","DOI":"10.1006\/meth.2001.1262"},{"doi-asserted-by":"publisher","key":"e_1_2_7_12_1","DOI":"10.1152\/ajpendo.00064.2016"},{"doi-asserted-by":"publisher","key":"e_1_2_7_13_1","DOI":"10.1177\/00033197211005590"},{"doi-asserted-by":"publisher","key":"e_1_2_7_14_1","DOI":"10.2337\/dc14\u20102629"},{"doi-asserted-by":"publisher","key":"e_1_2_7_15_1","DOI":"10.1016\/j.pharmthera.2011.11.003"},{"doi-asserted-by":"publisher","key":"e_1_2_7_16_1","DOI":"10.1111\/j.1540\u20108167.2006.00401.x"},{"doi-asserted-by":"publisher","key":"e_1_2_7_17_1","DOI":"10.2337\/db13\u20101562"},{"doi-asserted-by":"publisher","key":"e_1_2_7_18_1","DOI":"10.1016\/j.cmet.2008.09.008"},{"doi-asserted-by":"publisher","key":"e_1_2_7_19_1","DOI":"10.1038\/nm.4346"},{"doi-asserted-by":"publisher","key":"e_1_2_7_20_1","DOI":"10.1242\/dmm.006239"}],"container-title":["Basic &amp; 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