{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T22:45:45Z","timestamp":1792363545167,"version":"4.4.0"},"reference-count":70,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T00:00:00Z","timestamp":1713484800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2019\u201001066"],"award-info":[{"award-number":["2019\u201001066"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2022\u201000562"],"award-info":[{"award-number":["2022\u201000562"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005375","name":"Latvijas Zin\u0101tnes Padome","doi-asserted-by":"publisher","award":["LZP\u20102023\/1\u20100287"],"award-info":[{"award-number":["LZP\u20102023\/1\u20100287"]}],"id":[{"id":"10.13039\/501100005375","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["857394"],"award-info":[{"award-number":["857394"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010661","name":"Horizon 2020 Framework Programme","doi-asserted-by":"publisher","award":["857287"],"award-info":[{"award-number":["857287"]}],"id":[{"id":"10.13039\/100010661","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>\n                      Statins are competitive inhibitors of 3\u2010hydroxy\u20103\u2010methylglutaryl coenzyme A (HMG\u2010CoA) reductase (HMGCR), and exert adverse effects on mitochondrial function, although the mechanisms underlying these effects remain unclear. We used a tamoxifen\u2010induced\n                      <jats:italic>Hmgcr<\/jats:italic>\n                      \u2010knockout (KO) mouse model, a multi\u2010omics approach and mitochondrial function assessments to investigate whether decreased HMGCR activity impacts key liver energy metabolism pathways.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      We established a new mouse strain using the Cre\/loxP system, which enabled whole\u2010body deletion of\n                      <jats:italic>Hmgcr<\/jats:italic>\n                      expression. These mice were crossed with Rosa26\n                      <jats:sup>Cre<\/jats:sup>\n                      mice and treated with tamoxifen to delete\n                      <jats:italic>Hmgcr<\/jats:italic>\n                      in all cells. We performed transcriptomic and metabolomic analyses and thus evaluated time\u2010dependent changes in metabolic functions to identify the pathways leading to cell death in\n                      <jats:italic>Hmgcr<\/jats:italic>\n                      \u2010KO mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Lack of\n                      <jats:italic>Hmgcr<\/jats:italic>\n                      expression resulted in lethality, due to acute liver damage caused by rapid disruption of mitochondrial fatty acid \u03b2\u2010oxidation and very high accumulation of long\u2010chain (LC) acylcarnitines in both male and female mice. Gene expression and KO\u2010related phenotype changes were not observed in other tissues. The progression to liver failure was driven by diminished peroxisome formation, which resulted in impaired mitochondrial and peroxisomal fatty acid metabolism, enhanced glucose utilization and whole\u2010body hypoglycaemia.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Our findings suggest that HMGCR is crucial for maintaining energy metabolism balance, and its activity is necessary for functional mitochondrial \u03b2\u2010oxidation. Moreover, statin\u2010induced adverse reactions might be rescued by the prevention of LC acylcarnitine accumulation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.16363","type":"journal-article","created":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T02:44:55Z","timestamp":1713581095000},"page":"2750-2773","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hydroxymethylglutaryl\u2010CoA reductase activity is essential for mitochondrial \u03b2\u2010oxidation of fatty acids to prevent lethal accumulation of long\u2010chain acylcarnitines in the mouse liver"],"prefix":"10.1111","volume":"181","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2213-8337","authenticated-orcid":false,"given":"Edgars","family":"Liepinsh","sequence":"first","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"},{"name":"Riga Stradins University  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4576-2386","authenticated-orcid":false,"given":"Liga","family":"Zvejniece","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Clemensson","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melita","family":"Ozola","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"},{"name":"Riga Stradins University  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edijs","family":"Vavers","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Cirule","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanislava","family":"Korzh","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Skuja","sequence":"additional","affiliation":[{"name":"Riga Stradins University  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerija","family":"Groma","sequence":"additional","affiliation":[{"name":"Riga Stradins University  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monta","family":"Briviba","sequence":"additional","affiliation":[{"name":"Latvian Biomedical Research and Study Centre  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solveiga","family":"Grinberga","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Liu","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawe\u0142","family":"Olszewski","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lissa","family":"Gentreau","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Fredriksson","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maija","family":"Dambrova","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis  Riga Latvia"},{"name":"Riga Stradins University  Riga Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helgi B.","family":"Schi\u00f6th","sequence":"additional","affiliation":[{"name":"Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2015.10.079"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15542"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13882"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2010.11.006"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1815150116"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF02522982"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2013.05.001"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2007.11.001"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bty560"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-81846-9"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.118.010376"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15868"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/pharmrev.121.000408"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.RA120001006"},{"issue":"4","key":"e_1_2_12_16_1","first-page":"429","article-title":"The interaction between statins and exercise: Mechanisms and strategies to counter the musculoskeletal side effects of this combination therapy","volume":"15","author":"Deichmann R. E.","year":"2015","journal-title":"The Ochsner Journal"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2022.06.001"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10010194"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21020578"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2005.06.001"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2015.01.036"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymgme.2017.05.003"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2020.165720"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.3390\/antiox11020192"},{"key":"e_1_2_12_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11154-018-9448-1"},{"key":"e_1_2_12_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbalip.2012.02.011"},{"key":"e_1_2_12_27_1","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2017.221"},{"key":"e_1_2_12_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-9861(88)90455-9"},{"key":"e_1_2_12_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkz114"},{"key":"e_1_2_12_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/biof.1378"},{"key":"e_1_2_12_31_1","doi-asserted-by":"publisher","DOI":"10.1042\/BCJ20160164"},{"key":"e_1_2_12_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00210-013-0849-0"},{"key":"e_1_2_12_33_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15178"},{"key":"e_1_2_12_34_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"e_1_2_12_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2015.129"},{"key":"e_1_2_12_36_1","doi-asserted-by":"publisher","DOI":"10.2478\/rjim-2021-0021"},{"key":"e_1_2_12_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-29363-9"},{"key":"e_1_2_12_38_1","doi-asserted-by":"publisher","DOI":"10.21037\/atm.2018.10.57"},{"key":"e_1_2_12_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12654"},{"key":"e_1_2_12_40_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.111.240754"},{"key":"e_1_2_12_41_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATV.0000000000000073"},{"key":"e_1_2_12_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0022-3476(95)70073-0"},{"key":"e_1_2_12_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-60204-8_1"},{"key":"e_1_2_12_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1388-1981(02)00296-2"},{"key":"e_1_2_12_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2015.09.065"},{"key":"e_1_2_12_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab382"},{"key":"e_1_2_12_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjcard.2011.08.045"},{"key":"e_1_2_12_48_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.12960"},{"key":"e_1_2_12_49_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000410"},{"key":"e_1_2_12_50_1","doi-asserted-by":"publisher","DOI":"10.3109\/03602532.2011.604086"},{"key":"e_1_2_12_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0089-3"},{"key":"e_1_2_12_52_1","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e31816ff6f0"},{"key":"e_1_2_12_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature01667"},{"key":"e_1_2_12_54_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.72.121801.161712"},{"key":"e_1_2_12_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.08.002"},{"key":"e_1_2_12_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0009-6"},{"key":"e_1_2_12_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep00079"},{"key":"e_1_2_12_58_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-009-1125-9"},{"key":"e_1_2_12_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00438.2013"},{"key":"e_1_2_12_60_1","doi-asserted-by":"publisher","DOI":"10.2337\/db19-0996"},{"key":"e_1_2_12_61_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01307.2007"},{"key":"e_1_2_12_62_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7342"},{"key":"e_1_2_12_63_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.20.5.1868-1876.2000"},{"key":"e_1_2_12_64_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0009-8981(98)00188-0"},{"key":"e_1_2_12_65_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.028503"},{"key":"e_1_2_12_66_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.20567"},{"key":"e_1_2_12_67_1","doi-asserted-by":"publisher","DOI":"10.12997\/jla.2020.9.3.313"},{"key":"e_1_2_12_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xinn.2021.100141"},{"key":"e_1_2_12_69_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80611-X"},{"key":"e_1_2_12_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2018.10.019"},{"key":"e_1_2_12_71_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10092195"}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.16363","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/bph.16363","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/bph.16363","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:39:58Z","timestamp":1790131198000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1111\/bph.16363"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,19]]},"references-count":70,"journal-issue":{"issue":"16","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1111\/bph.16363"],"URL":"https:\/\/doi.org\/10.1111\/bph.16363","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,19]]},"assertion":[{"value":"2023-09-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-01-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}